Immunotherapy design - ACIR Journal Articles

TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors

(1) Eggeb¿ MS (2) Heinzelbecker J (3) Palashati H (4) Chandler N (5) Tran TT (6) Li Y (7) Yang W (8) Laos M (9) Blaas I (10) Rustad EH (11) Bollineni RC (12) Delic-Sarac M (13) Lund-Johansen F (14) Nielsen MM (15) Olweus J

Nature immunology

CTNNB1^S37F (CTNNB1^WT encodes β-catenin) is a driver mutation found across solid tumors. Using an HLA⁺ cell line transduced with CTNNB1^S37F, Eggebø et al. used MS to identify two HLA-bound neopeptides that were also expressed naturally on CTNNB1^S37F⁺ tumor cells. Priming naive CD8⁺ T cells with these neoantigens identified 4 reactive TCRs that were highly specific, recognizing CTNNB1^S37F with pM-nM affinity, but not CTNNB1^WT or similar off-target peptides. TCR T cells expressing these TCRs eliminated patient-derived tumor organoids in vitro, and effectively treated CTNNB1^S37F⁺ melanoma and PDX endometrial adenocarcinoma in vivo.

Contributed by Alex Najibi

(1) Eggeb¿ MS (2) Heinzelbecker J (3) Palashati H (4) Chandler N (5) Tran TT (6) Li Y (7) Yang W (8) Laos M (9) Blaas I (10) Rustad EH (11) Bollineni RC (12) Delic-Sarac M (13) Lund-Johansen F (14) Nielsen MM (15) Olweus J

Nature immunology

CTNNB1^S37F (CTNNB1^WT encodes β-catenin) is a driver mutation found across solid tumors. Using an HLA⁺ cell line transduced with CTNNB1^S37F, Eggebø et al. used MS to identify two HLA-bound neopeptides that were also expressed naturally on CTNNB1^S37F⁺ tumor cells. Priming naive CD8⁺ T cells with these neoantigens identified 4 reactive TCRs that were highly specific, recognizing CTNNB1^S37F with pM-nM affinity, but not CTNNB1^WT or similar off-target peptides. TCR T cells expressing these TCRs eliminated patient-derived tumor organoids in vitro, and effectively treated CTNNB1^S37F⁺ melanoma and PDX endometrial adenocarcinoma in vivo.

Contributed by Alex Najibi

ABSTRACT: HLA-bound peptides encoded by recurrent driver mutations are candidate targets for T cell-directed immunotherapy. Here we identify two neopeptides encoded by the CTNNB1S37F mutation presented on the frequent HLA-A*02:01 and HLA-A*24:02 molecules in cell lines naturally expressing the mutation and HLA alleles. This mutation leads to a gain of function in β-catenin and is estimated to occur in >7,000 new cancer cases annually in the United States. T cell receptors (TCRs) that specifically recognize the mutant peptides were isolated from naive healthy donor T cells. T cells redirected with CTNNB1-S37F TCRs efficiently killed CTNNB1S37F+ cell lines and patient-derived organoids in vitro and eradicated established tumors in a melanoma cell line mouse model and a patient-derived xenograft model of endometrial adenocarcinoma naturally expressing the mutation and the restricting HLA. We propose that TCR-T cells targeting CTNNB1-S37F can serve as a basis for solid cancer immunotherapy.

Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department

Author Info: (1) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (2) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (3) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (4) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (5) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. (6) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (7) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (8) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (9) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (10) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (11) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (12) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. (13) The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. fridtjl@medisin.uio.no. Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway. fridtjl@medisin.uio.no. (14) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. m.m.nielsen@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. m.m.nielsen@medisin.uio.no. (15) Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway. johanna.olweus@medisin.uio.no. The Precision Immunotherapy Alliance, University of Oslo, Oslo, Norway. johanna.olweus@medisin.uio.no.

Citation: Nat Immunol 2025 Aug 27 Epub08/27/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40866620

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Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma

(1) Yang J (2) Wang C (3) Fu D (4) Ho LL (5) Galani K (6) Chen L (7) Gonzalez J (8) Fu J (9) Huang AY (10) Frederick DT (11) He L (12) Asnani M (13) Tacke R (14) Robitschek EJ (15) Yadav SK (16) Deng W (17) Burke KP (18) Sharova T (19) Sullivan RJ (20) Weiss S (21) Rai K (22) Liu D (23) Boland GM (24) Kellis M

Nature communications - Open Access | Free PMC Article

Yang, Wang, and Fu et al. profiled 15 responding and 21 non-responding metastatic melanoma tumors and identified 14 cell types and 55 subtypes, including a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC); correlation analysis identified six cellular programs. Higher relative abundance of mregDCs predicted responses to ICI treatment, which was validated in an independent ICI-treated cohort. High mregDC and TCF7⁺ CD8⁺ T cell proportions stratified patients’ survival across treatments. Transcriptional, epigenetic, and interactome analysis revealed unique immune-stimulatory and regulatory roles of mregDCs.

Contributed by Shishir Pant

(1) Yang J (2) Wang C (3) Fu D (4) Ho LL (5) Galani K (6) Chen L (7) Gonzalez J (8) Fu J (9) Huang AY (10) Frederick DT (11) He L (12) Asnani M (13) Tacke R (14) Robitschek EJ (15) Yadav SK (16) Deng W (17) Burke KP (18) Sharova T (19) Sullivan RJ (20) Weiss S (21) Rai K (22) Liu D (23) Boland GM (24) Kellis M

Nature communications - Open Access | Free PMC Article

Yang, Wang, and Fu et al. profiled 15 responding and 21 non-responding metastatic melanoma tumors and identified 14 cell types and 55 subtypes, including a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC); correlation analysis identified six cellular programs. Higher relative abundance of mregDCs predicted responses to ICI treatment, which was validated in an independent ICI-treated cohort. High mregDC and TCF7⁺ CD8⁺ T cell proportions stratified patients’ survival across treatments. Transcriptional, epigenetic, and interactome analysis revealed unique immune-stimulatory and regulatory roles of mregDCs.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet most patients fail to achieve durable responses. To better understand the tumor microenvironment (TME), we analyze single-cell RNA-seq (~189_K cells) from 36 metastatic melanoma samples, defining 14 cell types, 55 subtypes, and 15 transcriptional hallmarks of malignant cells. Correlations between cell subtype proportions reveal six distinct clusters, with a mature dendritic cell subtype enriched in immunoregulatory molecules (mregDC) linked to naive T and B cells. Importantly, mregDC abundance predicts progression-free survival (PFS) with ICIs and other therapies, especially when combined with the TCF7_+_/- CD8 T cell ratio. Analysis of an independent cohort (n_=_318) validates mregDC as a predictive biomarker for anti-CTLA-4 plus anti-PD-1 therapies. Further characterization of mregDCs versus conventional dendritic cells (cDC1/cDC2) highlights their unique transcriptional, epigenetic (single-nucleus ATAC-seq data for cDCs from 14 matched samples), and interaction profiles, offering new insights for improving immunotherapy response and guiding future combination treatments.

Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard,

Author Info: (1) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. jackie.yang@rutgers.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. jackie.yang@rutgers.edu. Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. jackie.yang@rutgers.edu. (2) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (8) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Division of Medical Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (11) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Department of Genetics, School of Arts and Sciences, Rutgers University-New Brunswick, Piscataway, NJ, USA. Human Genetics Institute of New Jersey, Rutgers University-New Brunswick, Piscataway, NJ, USA. (13) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (15) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (18) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA. Division of Hematology and Oncology, Department of Medicine, Mass General Brigham, Boston, MA, USA. (20) Medical Oncology, Rutgers Cancer Institute, New Brunswick, NJ, USA. (21) Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. GMBOLAND@MGH.HARVARD.EDU. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Mass General Brigham, Boston, MA, USA. GMBOLAND@MGH.HARVARD.EDU. (24) Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. manoli@mit.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. manoli@mit.edu.

Citation: Nat Commun 2025 Sep 1 16:8151 Epub09/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40890106

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A novel CD3ε fusion receptor allows T cell engager use in TCR-less allogeneic CAR T cells to improve activity and prevent antigen escape

(1) Lu D (2) Chu HY (3) Park S (4) Landon M (5) Tsuda M (6) Avramis E (7) Dege C (8) Dailey T (9) Pan Y (10) Hanok SK (11) Denholtz M (12) Abujarour R (13) Lee T (14) Goulding J (15) Hosking M (16) Goodridge J (17) Peralta E (18) Valamehr B

Molecular therapy | Free PMC Article

TCR KO supports allogeneic CAR T cells, but also results in CD3 antigen loss from the cell surface. Lu et al. engineered a CD3ε fusion receptor (CD3FR) that could be expressed on TCR- cells and engaged with T cell engagers (TCEs) for T cell signaling and activation. Via CAR and TCEs, iPSC-derived TCR^- CD3FR⁺ CAR T cells could target one or multiple tumor antigens to improve cytotoxicity over control CAR T cells in vitro (especially at low E:T and with repeated stimulation) and in vivo, including against heterogeneous tumors. CD3FR⁺ CAR T cells secreting TCEs showed enhanced cytotoxicity and engaged bystander T cells. The CD3FR-TCE strategy also improved CAR iNK cell efficacy.

Contributed by Alex Najibi

(1) Lu D (2) Chu HY (3) Park S (4) Landon M (5) Tsuda M (6) Avramis E (7) Dege C (8) Dailey T (9) Pan Y (10) Hanok SK (11) Denholtz M (12) Abujarour R (13) Lee T (14) Goulding J (15) Hosking M (16) Goodridge J (17) Peralta E (18) Valamehr B

Molecular therapy | Free PMC Article

TCR KO supports allogeneic CAR T cells, but also results in CD3 antigen loss from the cell surface. Lu et al. engineered a CD3ε fusion receptor (CD3FR) that could be expressed on TCR- cells and engaged with T cell engagers (TCEs) for T cell signaling and activation. Via CAR and TCEs, iPSC-derived TCR^- CD3FR⁺ CAR T cells could target one or multiple tumor antigens to improve cytotoxicity over control CAR T cells in vitro (especially at low E:T and with repeated stimulation) and in vivo, including against heterogeneous tumors. CD3FR⁺ CAR T cells secreting TCEs showed enhanced cytotoxicity and engaged bystander T cells. The CD3FR-TCE strategy also improved CAR iNK cell efficacy.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in treating hematologic malignancies. However, heterogeneous target antigen expression can impair the durability of response. Combining CAR and T cell engagers (TCEs) targeting additional tumor antigens can address tumor heterogeneity and antigen escape. In allogeneic settings, eliminating the T cell receptor (TCR) of the adoptive T cell therapy prevents graft-versus-host disease. However, the absence of TCR leads to loss of surface CD3 expression, preventing cooperative activity with CD3-directed TCEs. We utilized induced pluripotent stem cells (iPSCs) to support the required multiplexed editing, establish a renewable starting material for off-the-shelf manufacture, and create the desired TCR-less CAR+ CD3+ T cells. Here, we illustrate surface expression of a CD3ε fusion receptor (CD3FR) in iPSC-derived CAR T (CAR iT) cells, enabling TCE-mediated targeting of diverse antigens. In vitro and in vivo, CD3FR+ CAR iT cells demonstrated potent cytotoxic response and cooperative activity against mixed tumor lines and multiple antigens. CD3FR+ iT cells were further engineered to secrete TCEs, eliminating the need for extra supplementation with TCEs. Collectively, the data highlight the ability to integrate TCEs with allogeneic CAR iT cells for multi-antigen targeting, overcoming tumor relapse, and supporting off-the-shelf therapy for patient access.

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therap

Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (5) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (6) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (7) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (8) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (9) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (10) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (11) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (12) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (13) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (14) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (15) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (16) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (17) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: eigen.peralta@fatetherapeutics.com. (18) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: bob.valamehr@fatetherapeutics.com.

Citation: Mol Ther 2025 Sep 3 33:4570-4583 Epub05/28/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40443031

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Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors

(1) Abrantes R (2) Forcados C (3) Warren DJ (4) Santos-Ferreira L (5) Fleten KG (6) Senra E (7) Costa AF (8) Krpina K (9) Henrique R (10) Liberg AM (11) Rawat P (12) Gelebart P (13) McCormack E (14) Bj¿rge L (15) Davidson B (16) Greiff V (17) Costea DE (18) Pinto F (19) Flatmark K (20) Gomes C (21) Inderberg EM (22) Reis CA (23) Wlchli S

Cell reports. Medicine - Open Access

Abrantes and Forcados et al. generated and characterized AM52.1, a pan-carcinoma antibody with exclusive specificity for a truncated O-glycan structure Sialyl-Tn antigen (STn), which is found on various epithelial tumors, but not healthy tissues, and is associated with adverse outcomes. AM52.1 CAR T cells efficiently targeted STn-expressing cell lines and patient-derived organoids, and significantly extended survival in preclinical models of gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases. AM52.1 CAR T cells eradicated STn-positive tumor cells, even at low antigen density, with no evidence of toxicity.

Contributed by Katherine Turner

(1) Abrantes R (2) Forcados C (3) Warren DJ (4) Santos-Ferreira L (5) Fleten KG (6) Senra E (7) Costa AF (8) Krpina K (9) Henrique R (10) Liberg AM (11) Rawat P (12) Gelebart P (13) McCormack E (14) Bj¿rge L (15) Davidson B (16) Greiff V (17) Costea DE (18) Pinto F (19) Flatmark K (20) Gomes C (21) Inderberg EM (22) Reis CA (23) Wlchli S

Cell reports. Medicine - Open Access

Abrantes and Forcados et al. generated and characterized AM52.1, a pan-carcinoma antibody with exclusive specificity for a truncated O-glycan structure Sialyl-Tn antigen (STn), which is found on various epithelial tumors, but not healthy tissues, and is associated with adverse outcomes. AM52.1 CAR T cells efficiently targeted STn-expressing cell lines and patient-derived organoids, and significantly extended survival in preclinical models of gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases. AM52.1 CAR T cells eradicated STn-positive tumor cells, even at low antigen density, with no evidence of toxicity.

Contributed by Katherine Turner

ABSTRACT: Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.

Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Mole

Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (2) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (3) Department of Medical Biochemistry, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (4) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (5) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway. (6) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (7) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (8) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway. (9) ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Department of Pathology & Cancer Biology and Epigenetics Group - Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (P.CCC), Rua Dr. Antnio Bernardino de Almeida, 4200-072 Porto, Portugal. (10) Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (11) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (12) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (13) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Hematology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (14) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (15) Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway; Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (16) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (17) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Gade Laboratory for Pathology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (18) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (19) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Department of Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (20) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (21) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (22) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernni Monteiro, 4200-319 Porto, Portugal. Electronic address: celsor@i3s.up.pt. (23) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. Electronic address: sebastw@ous-hf.no.

Citation: Cell Rep Med 2025 Sep 1 102350 Epub09/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40925376

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Functional genetic screens reveal key pathways instructing the molecular phenotypes of tumor-associated macrophages

(1) Lu Y (2) Luo C (3) Huang L (4) Wu G (5) Zhong L (6) Chu J (7) Wang F (8) Zeng Z (9) Pan D

Cancer immunology research

Lu and Luo et al. performed CRISPR screens in primary macrophages and identified lactic acid, PGE2, and GM-CSF as tumor-derived modulators of TAM polarization. Lactic acid and PGE2 cooperatively induced angiogenic programs while suppressing MHC-II expression, whereas GM-CSF promoted MHC-II^hi TAMs. Angiogenic TAMs were present in hypoxic regions, and MHC-II^hi TAMs were in normoxic areas, creating mutually exclusive spatial niches in the TME. Deletion of Adar, an RNA-editing enzyme, reshaped TAMs into an “interferon-stimulated gene” state associated with T cell mediated antitumor immunity.

Contributed by Shishir Pant

(1) Lu Y (2) Luo C (3) Huang L (4) Wu G (5) Zhong L (6) Chu J (7) Wang F (8) Zeng Z (9) Pan D

Cancer immunology research

Lu and Luo et al. performed CRISPR screens in primary macrophages and identified lactic acid, PGE2, and GM-CSF as tumor-derived modulators of TAM polarization. Lactic acid and PGE2 cooperatively induced angiogenic programs while suppressing MHC-II expression, whereas GM-CSF promoted MHC-II^hi TAMs. Angiogenic TAMs were present in hypoxic regions, and MHC-II^hi TAMs were in normoxic areas, creating mutually exclusive spatial niches in the TME. Deletion of Adar, an RNA-editing enzyme, reshaped TAMs into an “interferon-stimulated gene” state associated with T cell mediated antitumor immunity.

Contributed by Shishir Pant

ABSTRACT: Tumor-associated macrophages (TAMs) display remarkable functional heterogeneity, yet the molecular mechanisms driving their diverse phenotypes remain elusive. Using CRISPR screens in primary macrophages, we identified tumor-derived factors, including lactic acid, PGE2, and GM-CSF, as key modulators of TAM polarization. These factors interact synergistically and antagonistically to shape distinct TAM phenotypes that are highly conserved across human cancers. Mechanistically, lactic acid and PGE2 jointly induce angiogenic gene programs while suppressing GM-CSF-driven MHC-II expression at the chromatin level, creating mutually exclusive distributions of proangiogenic and MHC-II+ TAMs, which are differentially localized to specific spatial niches in the tumor microenvironment. Furthermore, we showed that shifting TAMs to an interferon-responsive phenotype, triggered by Adar inactivation, significantly promotes the infiltration of effector CD8+ T cells through specific receptor-ligand interactions. These findings uncover a conserved mechanism of TAM polarization and offer insights into therapeutic strategies for TAM reprogramming to potentiate cancer immunotherapy.

Author Info: (1) Tsinghua University, Beijing, Beijing, China. (2) Peking University, Beijing, China. (3) Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China. (4) Tsinghua University, Be

Author Info: (1) Tsinghua University, Beijing, Beijing, China. (2) Peking University, Beijing, China. (3) Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China. (4) Tsinghua University, Beijing, Beijing, China. (5) Tsinghua University, Beijing, Beijing, China. (6) Peking University, Beijing, Beijing, China. (7) Zhongnan Hospital of Wuhan University, Wuhan, Hubei province, China. (8) Dana-Farber Cancer Institute, Boston, United States. (9) Tsinghua University, Beijing, Beijing, China.

Citation: Cancer Immunol Res 2025 Sep 4 Epub09/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40906823

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Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer

(1) Rivadeneira DB (2) Thosar S (3) Quann K (4) Gunn WG (5) Dean VG (6) Xie B (7) Parise A (8) McGovern AC (9) Spahr K (10) Lontos K (11) Barnes RP (12) Bruchez MP (13) Opresko PL (14) Delgoffe GM

Immunity - Open Access

Rivadeneira et al. assessed the role of oxidative damage on T cell function in the TME. Oxidative stress in mitochondria resulted in reduced T cell proliferation, terminal differentiation, and dysfunction. DNA damage at telomeres was found to be responsible for these effects. Alleviating oxidative stress at telomeres with a ROS scavenger fusion protein could enhance T cell functionality and prevent formation of dysfunctional phenotype, improving tumor control in vivo.

(1) Rivadeneira DB (2) Thosar S (3) Quann K (4) Gunn WG (5) Dean VG (6) Xie B (7) Parise A (8) McGovern AC (9) Spahr K (10) Lontos K (11) Barnes RP (12) Bruchez MP (13) Opresko PL (14) Delgoffe GM

Immunity - Open Access

Rivadeneira et al. assessed the role of oxidative damage on T cell function in the TME. Oxidative stress in mitochondria resulted in reduced T cell proliferation, terminal differentiation, and dysfunction. DNA damage at telomeres was found to be responsible for these effects. Alleviating oxidative stress at telomeres with a ROS scavenger fusion protein could enhance T cell functionality and prevent formation of dysfunctional phenotype, improving tumor control in vivo.

ABSTRACT: The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.

Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dar177@pitt.edu. (2) Department of Cancer Biology, University of Kansas Medical Cen

Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dar177@pitt.edu. (2) Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. (3) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (9) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (10) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (11) Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. (12) Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA. (13) Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: gdelgoffe@pitt.edu.

Citation: Immunity 2025 Sep 3 Epub09/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40930086

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Cytotoxic CD4⁺ T cells exhibit an immunosuppressive shift in checkpoint immunotherapy resistance in melanoma patients

(1) Bae HR (2) Son B (3) Hwang K (4) Kim S (5) Young HA (6) Kwon EY

Cancer immunology, immunotherapy - Open Access | Free PMC Article

Using scRNAseq data from patients with ICI-treated melanoma, Bae et al. profiled conventional CD4⁺ T cells (excluding Tregs and proliferative cells) at the lesion level. A cytotoxic cluster was enriched in responders, and an exhausted, Treg-like cluster was detected in all samples, and trended towards enrichment in non-responders (NRs). Two clusters dually enhanced in cytotoxicity and exhaustion genes also trended towards enrichment in NRs. Trajectory analysis suggested a cluster characterized by migratory genes as a precursor to the cytotoxic/exhausted clusters, along with a potential transition of a unique exhausted cluster to the Treg-like state.

Contributed by Morgan Janes

(1) Bae HR (2) Son B (3) Hwang K (4) Kim S (5) Young HA (6) Kwon EY

Cancer immunology, immunotherapy - Open Access | Free PMC Article

Using scRNAseq data from patients with ICI-treated melanoma, Bae et al. profiled conventional CD4⁺ T cells (excluding Tregs and proliferative cells) at the lesion level. A cytotoxic cluster was enriched in responders, and an exhausted, Treg-like cluster was detected in all samples, and trended towards enrichment in non-responders (NRs). Two clusters dually enhanced in cytotoxicity and exhaustion genes also trended towards enrichment in NRs. Trajectory analysis suggested a cluster characterized by migratory genes as a precursor to the cytotoxic/exhausted clusters, along with a potential transition of a unique exhausted cluster to the Treg-like state.

Contributed by Morgan Janes

ABSTRACT: Although checkpoint immunotherapy has primarily focused on CD8⁺ T cells, emerging evidence highlights an important role for cytotoxic CD4⁺ T cells in mediating therapeutic responses. However, research on the functional properties of cytotoxic CD4⁺ T cells in the context of immunotherapy is still at an early stage and remains insufficiently defined. Utilizing single-cell RNA-sequencing datasets obtained from metastatic melanoma patients treated with checkpoint inhibitors targeting PD-1 and/or CTLA-4, we performed transcriptomic profiling of conventional CD4⁺ T cells, excluding proliferative and regulatory (FOXP3⁺) subsets, and compared responders and non-responders as distinct groups. Importantly, our analysis identified distinct clusters that discriminate between responders and non-responders, with cytotoxic CD4⁺ T cells occupying a central position within these clusters. In responder-specific clusters, cytotoxic CD4⁺ T cells exhibited features of early activation, whereas clusters specific to non-responders were characterized by an exhausted phenotype. Notably, non-responder-specific clusters were positioned proximally to Treg-like clusters, suggesting a potential transition from cytotoxic to regulatory CD4⁺ T cell states in non-responders. Our findings reinforce the emerging concept that cytotoxic CD4⁺ T cells play a central role in mediating immunotherapy responses. These results provide a foundation for the development of predictive biomarkers and novel therapeutic strategies aimed at modulating CD4⁺ T cell differentiation.

Author Info: (1) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. Department of Food Science and Nutrition, Kyungpook National Universit

Author Info: (1) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea. Omixplus, LLC, Austin, TX, 78750, USA. (2) Department of Biology, Kyungpook National University, Daegu, 41566, Republic of Korea. (3) School of Artificial Intelligence, Kyungpook National University, Daegu, 41566, Republic of Korea. (4) Omixplus, LLC, Austin, TX, 78750, USA. (5) Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA. (6) Center for Food and Nutritional Genomics, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr. Department of Food Science and Nutrition, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr. Center for Beautiful Aging, Kyungpook National University, Daegu, 41566, Republic of Korea. eykwon@knu.ac.kr.

Citation: Cancer Immunol Immunother 2025 Sep 4 74:297 Epub09/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40906211

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Engineered T cells stimulate dendritic cell recruitment and antigen spreading for potent anti-tumor immunity Spotlight

(1) Xiao Z (2) Wang J (3) He S (4) Wang L (5) Yang J (6) Li W (7) Ma K (8) Zhou Y (9) Liu X (10) Wang S (11) Yang Y (12) Ge M (13) Gao A (14) Tang K (15) Huang J (16) Wang C (17) Zhang L (18) Sun HX (19) Zhang L

Cell reports. Medicine - Open Access

Focusing on antigenic heterogeneity and antigen loss in solid tumors, Xiao, Wang, and He et al. engineered T cells to express FLT3L and XCL1 (FX). Adoptively transferred FX T cells improved DC recruitment and activation in the TME (increased IFNγ and IL-12), inducing antigen spreading and potent polyclonal T cell responses, and resulting in control and elimination of antigenic heterogeneous tumors and prevention of immune escape. XCL1 expression positively correlated with a CD8⁺ Tpex signature in mouse and human tumors, and with patient survival and response to ICB. FX-CAR T cells also exhibited superior tumor control in humanized mice.

Contributed by Katherine Turner

(1) Xiao Z (2) Wang J (3) He S (4) Wang L (5) Yang J (6) Li W (7) Ma K (8) Zhou Y (9) Liu X (10) Wang S (11) Yang Y (12) Ge M (13) Gao A (14) Tang K (15) Huang J (16) Wang C (17) Zhang L (18) Sun HX (19) Zhang L

Cell reports. Medicine - Open Access

Focusing on antigenic heterogeneity and antigen loss in solid tumors, Xiao, Wang, and He et al. engineered T cells to express FLT3L and XCL1 (FX). Adoptively transferred FX T cells improved DC recruitment and activation in the TME (increased IFNγ and IL-12), inducing antigen spreading and potent polyclonal T cell responses, and resulting in control and elimination of antigenic heterogeneous tumors and prevention of immune escape. XCL1 expression positively correlated with a CD8⁺ Tpex signature in mouse and human tumors, and with patient survival and response to ICB. FX-CAR T cells also exhibited superior tumor control in humanized mice.

Contributed by Katherine Turner

ABSTRACT: Current T cell-based immunotherapeutic strategies show limited success in treating solid tumors due to insufficient dendritic cell (DC) activity, particularly cross-presenting conventional type 1 dendritic cells (cDC1s). DC scarcity and dysfunction hinder T cell expansion and differentiation, greatly limiting anti-tumor responses. In this study, we propose a T cell engineering strategy to enhance interaction with XCR1(+) cDC1s. Adoptively transferred T cells engineered to secrete Flt3L and XCL1 (FX) promote DC trafficking and maturation and improve DC-T cell interaction, while maintaining a pool of TCF1(+)SlamF6(+) stem-like T cells. Importantly, FX-engineered T cells trigger robust antigen spreading and potent endogenous polyclonal T cell response, enabling the recognition and elimination of tumors with heterogeneous antigens and preventing immune escape. The therapeutic efficacy of FX-armed chimeric antigen receptor (CAR)-T cells is further validated in the Flt3KO&hFLT3LG humanized mouse model. This strategy offers a promising avenue for enhancing DC-T cell interactions, paving the way for more effective immunotherapy against solid tumors.

Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu

Author Info: (1) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (2) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (3) College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. (4) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (5) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (6) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (7) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (8) Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China. (9) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (10) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (11) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215123, China. (12) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (13) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (14) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. (15) Nextvivo (Suzhou) Biotech Corp, Suzhou, Jiangsu 215123, China. (16) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: wc@ism.pumc.edu.cn. (17) Center for Cancer Diagnosis and Treatment, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China; PRAG Therapy Center, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zhangliyuan@suda.edu.cn. (18) College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: sunhaixi@genomics.cn. (19) National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: zlj@ism.cams.cn.

Citation: Cell Rep Med 2025 Aug 20 102307 Epub08/20/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40858102

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Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity Spotlight

(1) Henriques-Oliveira L (2) Altman AR (3) Kurochkin I (4) Ascic E (5) Halitzki E (6) Matei AM (7) Prtiga-Cabral D (8) Ulmert I (9) Holst S (10) Nair MS (11) Cunha PP (12) Park SM (13) Vergani S (14) Kharas MG (15) Yuan J (16) Lahl K (17) Rosa FF (18) Pires CF (19) Pereira CF

Immunity - Open Access

Using a sequential anchored transcription factor screen, Henriques-Oliveira, Altman, and Kurochkin et al. identified two transcription factor triads: PU.1, IRF4, and PRDM1 as inducers of cells similar to type 2 conventional DCs, and SPIB, IRF8, and IKZF2 as inducers of plasmacytoid DC-like cells. Chromatin remodeling at subset-specific sites drove the lineage divergence, each displaying specific phenotypes and functional properties. In vivo reprogramming of cancer cells into distinct DC subtypes showed distinct subset-specific antitumor immunity and durable memory responses in YUMM1.7 melanoma and EO771 breast cancer models.

Contributed by Shishir Pant

(1) Henriques-Oliveira L (2) Altman AR (3) Kurochkin I (4) Ascic E (5) Halitzki E (6) Matei AM (7) Prtiga-Cabral D (8) Ulmert I (9) Holst S (10) Nair MS (11) Cunha PP (12) Park SM (13) Vergani S (14) Kharas MG (15) Yuan J (16) Lahl K (17) Rosa FF (18) Pires CF (19) Pereira CF

Immunity - Open Access

Using a sequential anchored transcription factor screen, Henriques-Oliveira, Altman, and Kurochkin et al. identified two transcription factor triads: PU.1, IRF4, and PRDM1 as inducers of cells similar to type 2 conventional DCs, and SPIB, IRF8, and IKZF2 as inducers of plasmacytoid DC-like cells. Chromatin remodeling at subset-specific sites drove the lineage divergence, each displaying specific phenotypes and functional properties. In vivo reprogramming of cancer cells into distinct DC subtypes showed distinct subset-specific antitumor immunity and durable memory responses in YUMM1.7 melanoma and EO771 breast cancer models.

Contributed by Shishir Pant

ABSTRACT: Transcription factor cooperation is essential for specifying the heterogeneous dendritic cell (DC) lineages that orchestrate adaptive immunity, yet how it drives subset diversification remains poorly understood. Here, we employed a sequential anchored screen of 70 transcription factors using direct cellular reprogramming to identify regulators that specify type 2 conventional DCs (cDC2s) and plasmacytoid DCs (pDCs). We identified PU.1, IRF4, and PRDM1 as inducers of a pro-inflammatory cDC2B-like fate and SPIB, IRF8, and IKZF2 as mediators of an immature lymphoid DC program. Transcriptomic profiling linked these triads to lineage-specific signatures and demonstrated their requirement for subset identity. Mechanistically, lineage divergence was driven by chromatin co-engagement at subset-specific sites early in reprogramming. Functionally, reprogrammed DCs employed distinct immune mechanisms to elicit orthogonal anti-tumor responses in different tumor models. Collectively, our findings uncover transcriptional circuits that control DC diversification and pave the way to generate patient-tailored DC subsets for cancer immunotherapy.

Author Info: (1) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine

Author Info: (1) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, 3004-517 Coimbra, Portugal; University of Coimbra, Institute for Interdisciplinary Research, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Coimbra, Portugal. (2) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden. (3) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden. (4) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden. (5) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden. (6) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Asgard Therapeutics AB, Medicon Village, Lund 223 81, Sweden. (7) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, 3004-517 Coimbra, Portugal; University of Coimbra, Institute for Interdisciplinary Research, Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Coimbra, Portugal. (8) Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark. (9) Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark; Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 1N4, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. (10) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden. (11) Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, 3004-517 Coimbra, Portugal. (12) Molecular Pharmacology Program, Experimental Therapeutics Center, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Developmental Immunology Unit, Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, Lund 222 42, Sweden. (14) Molecular Pharmacology Program, Experimental Therapeutics Center, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Developmental Immunology Unit, Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, Lund 222 42, Sweden. (16) Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark, Kongens Lyngby 2800, Denmark; Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 1N4, Canada; Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Immunology Section, Lund University, Lund 221 84, Sweden. (17) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Asgard Therapeutics AB, Medicon Village, Lund 223 81, Sweden. (18) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Asgard Therapeutics AB, Medicon Village, Lund 223 81, Sweden. (19) Molecular Medicine and Gene Therapy, Science for Life Laboratory, Lund Stem Cell Centre, Lund University, BMC A12, Lund 221 84, Sweden; Wallenberg Centre for Molecular Medicine at Lund University, BMC A12, Lund 221 84, Sweden; Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, 3004-517 Coimbra, Portugal; Asgard Therapeutics AB, Medicon Village, Lund 223 81, Sweden. Electronic address: filipe.pereira@med.lu.se.

Citation: Immunity 2025 Aug 27 Epub08/27/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40885192

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Long-range deployment of tumor-antigen-specific cytotoxic T lymphocytes inhibits lung metastasis of breast cancer Spotlight

(1) Xing Y (2) Zhou Y (3) Wang R (4) Chen J (5) Yang L (6) Meng X (7) Wang J (8) Ouyang Q (9) Zhao J (10) Chen F (11) Saw PE (12) Fan J (13) Huang JD (14) Wu W (15) Liu Q (16) Song E (17) Huang D

Developmental cell

Xing, Zhou, and Wang et al. demonstrated the role of CD103⁺CD8⁺ T cells in protection against breast cancer lung metastasis. Tumor antigen-specific CD103⁺CD8⁺ T cells were primed in TDLNs, and recruited to the lungs. Extracellular vehicles from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively. CCL25/CCR9 signaling recruited tumor antigen-specific CD103⁺CD8⁺ T cells to the lung, whereas IDO1 impaired pulmonary CD103⁺CD8⁺ T cells to facilitate lung metastasis. IDO1 inhibition increased CD103⁺CD8⁺ T cell infiltration in the lungs and alleviated lung metastasis.

Contributed by Shishir Pant

(1) Xing Y (2) Zhou Y (3) Wang R (4) Chen J (5) Yang L (6) Meng X (7) Wang J (8) Ouyang Q (9) Zhao J (10) Chen F (11) Saw PE (12) Fan J (13) Huang JD (14) Wu W (15) Liu Q (16) Song E (17) Huang D

Developmental cell

Xing, Zhou, and Wang et al. demonstrated the role of CD103⁺CD8⁺ T cells in protection against breast cancer lung metastasis. Tumor antigen-specific CD103⁺CD8⁺ T cells were primed in TDLNs, and recruited to the lungs. Extracellular vehicles from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively. CCL25/CCR9 signaling recruited tumor antigen-specific CD103⁺CD8⁺ T cells to the lung, whereas IDO1 impaired pulmonary CD103⁺CD8⁺ T cells to facilitate lung metastasis. IDO1 inhibition increased CD103⁺CD8⁺ T cell infiltration in the lungs and alleviated lung metastasis.

Contributed by Shishir Pant

ABSTRACT: Tumor-antigen-specific CD8(+) T cells (CTLs) are the main effector immunocytes in anti-tumor immunity, but their systemic deployment against cancer metastasis remains uncharacterized. Here, we found that the abundance of tumor-specific CD103(+)CD8(+) T cells in the tumor-draining lymph nodes (TDLNs) was associated with improved lung-metastasis-free survival in breast cancer patients. In mouse cancer models, CD103(+)CD8(+) T cells were primed in TDLNs and recruited to the lungs via C-C motif chemokine ligand 5/receptor 9 (CCL25/CCR9) signaling to inhibit metastasis through antigen-specific immunity. Furthermore, extracellular vesicles (EVs) from early- and late-stage tumors differentially polarized alveolar macrophages to release CCL25 and IDO1, respectively, and the latter impaired pulmonary CD103(+)CD8(+) T cell deployment, facilitating lung metastasis. Depleting IDO1 effectively rescued CD103(+)CD8(+) T cell-mediated protection against lung metastasis. These findings exemplified long-range deployment of adaptive immunity to protect distant organs from metastasis, highlighting the therapeutic potential of reconstituting effector immune cell deployment (EICD) for cancer treatment.

Author Info: (1) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen

Author Info: (1) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (2) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (3) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (4) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (5) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (6) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (7) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (8) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (9) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (10) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (11) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (12) Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China. (13) School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. (14) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (15) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. (16) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China; Zenith Institute of Medical Sciences, Guangzhou, China. Electronic address: songew@mail.sysu.edu.cn. (17) Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: huangd63@mail.sysu.edu.cn.

Citation: Dev Cell 2025 Aug 22 Epub08/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40876455

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