Journal Articles

cGAS mRNA-Based Immune Agonist Promotes Vaccine Responses and Antitumor Immunity Spotlight 

(1) Qu Y (2) Li Z (3) Yin J (4) Huang H (5) Ma J (6) Jiang Z (7) Zhou Q (8) Tang Y (9) Li Y (10) Huang M (11) Zeng Z (12) Guo A (13) Fang F (14) Shen Y (15) Zhao R (16) Wang Y (17) Gao D

Cancer immunology research

Qu, Li et al. generated lipid nanoparticles (LNPs) encapsulating mRNA for cGAS, the innate immune sensor of cytoplasmic dsDNA. Human cGAS was mutated (K187N/L195R) to enhance its activation of the STING-dependent IFN response; induceAPC maturation, antigen uptake, and presentation; and upregulate expression of MHC-I, MHC-II, and costimulatory signals in vitro and in mice. Treating mice with mutated hcGASmRNA-LNPs induced strong innate and adaptive immune responses that boosted the potency of mRNA, protein, and tumor vaccines, and also synergized with IFNγ treatment to act directly on tumor cells to reduce tumor volume and increase host survival.

Contributed by Paula Hochman

(1) Qu Y (2) Li Z (3) Yin J (4) Huang H (5) Ma J (6) Jiang Z (7) Zhou Q (8) Tang Y (9) Li Y (10) Huang M (11) Zeng Z (12) Guo A (13) Fang F (14) Shen Y (15) Zhao R (16) Wang Y (17) Gao D

Cancer immunology research

Qu, Li et al. generated lipid nanoparticles (LNPs) encapsulating mRNA for cGAS, the innate immune sensor of cytoplasmic dsDNA. Human cGAS was mutated (K187N/L195R) to enhance its activation of the STING-dependent IFN response; induceAPC maturation, antigen uptake, and presentation; and upregulate expression of MHC-I, MHC-II, and costimulatory signals in vitro and in mice. Treating mice with mutated hcGASmRNA-LNPs induced strong innate and adaptive immune responses that boosted the potency of mRNA, protein, and tumor vaccines, and also synergized with IFNγ treatment to act directly on tumor cells to reduce tumor volume and increase host survival.

Contributed by Paula Hochman

ABSTRACT: mRNA vaccines are a potent tool for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. In this study, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNP), to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained stimulator of interferon gene (STING)-mediated IFN response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment, and antigen presentation by antigen-presenting cells, both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination demonstrated a robust adjuvant effect and amplified the potency of mRNA and protein vaccines, which was a result of strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted antitumor effects with IFN_ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.

Author Info: (1) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Cen

Author Info: (1) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (2) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (3) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (4) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (5) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (6) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (7) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (8) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (9) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (10) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (11) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (12) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (13) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (14) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (15) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (16) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (17) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China.

Citation: Cancer Immunol Res 2025 May 2 13:680-695 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40067177

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CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target Spotlight 

(1) Shukla D (2) Gabunia K (3) McGettigan SE (4) Patel PR (5) Christensen S (6) Fan TJ (7) Song D (8) Luo Y (9) Wang Y (10) Wang H (11) Young RM (12) June CH (13) Scholler J (14) Riley JL

Cancer immunology research

The murine anti-CD19 scFv FMC63 is employed in FDA-approved CAR T cell therapies. To reduce the potential for immunogenicity, Shukla et al. screened a library of fully human anti-CD19 scFvs for expression, functionality (CD19 binding and cytokine production), and tonic signaling. The best binders killed target cells in vitro, controlled tumors in vivo, and responded to low antigen densities. The top fully human scFv bound a different region of CD19 than FMC63, had weaker CD19 affinity (25nM vs. 0.6nM), and demonstrated comparable or superior in vitro tumor killing, CD19-low responses, and in vivo efficacy to FMC63, and is currently being tested in the clinic.

Contributed by Alex Najibi

(1) Shukla D (2) Gabunia K (3) McGettigan SE (4) Patel PR (5) Christensen S (6) Fan TJ (7) Song D (8) Luo Y (9) Wang Y (10) Wang H (11) Young RM (12) June CH (13) Scholler J (14) Riley JL

Cancer immunology research

The murine anti-CD19 scFv FMC63 is employed in FDA-approved CAR T cell therapies. To reduce the potential for immunogenicity, Shukla et al. screened a library of fully human anti-CD19 scFvs for expression, functionality (CD19 binding and cytokine production), and tonic signaling. The best binders killed target cells in vitro, controlled tumors in vivo, and responded to low antigen densities. The top fully human scFv bound a different region of CD19 than FMC63, had weaker CD19 affinity (25nM vs. 0.6nM), and demonstrated comparable or superior in vitro tumor killing, CD19-low responses, and in vivo efficacy to FMC63, and is currently being tested in the clinic.

Contributed by Alex Najibi

ABSTRACT: Patients can develop human anti-mouse immune responses against CD19-specific chimeric antigen receptor (CAR) T cells due to the use of a murine CD19-specific single-chain variable fragment to redirect T cells. We screened a yeast display library to identify an array of fully human CD19 single-chain variable fragment binders and performed a series of studies to select the most promising fully human CAR. We observed significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T-cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this initial analysis, CAR T cells using two binders (42 and 52) were selected for additional studies. Although CAR T cells using both binders controlled tumor growth well in vivo, we advanced a CAR construct using binder 42 for more advanced preclinical testing because of its greater similarity to binders based on the antibody FMC63, which is the murine antibody underlying four FDA-approved CD19-specific CAR T-cell therapies, and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 and with _40-fold lower affinity. CARs using binder 42 were non-inferior to those using the FMC63 binder in a mouse model of acute lymphoblastic leukemia, indicating that CAR T cells using binder 42 should be considered for clinical use.

Author Info: (1) Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania.

Author Info: (1) Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. (2) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (3) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (4) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (8) Tmunity Therapeutics/Kite Pharma, Philadelphia, Pennsylvania. (9) Tmunity Therapeutics/Kite Pharma, Philadelphia, Pennsylvania. (10) Tmunity Therapeutics/Kite Pharma, Philadelphia, Pennsylvania. (11) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (12) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania. (13) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (14) Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania. Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania.

Citation: Cancer Immunol Res 2025 Apr 29 OF1-OF14 Epub04/29/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40298385

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A dendritic cell-like transition of T cells is associated with spontaneous remission of adult T-cell leukemia-lymphoma Spotlight 

(1) Watanabe M (2) Yasunaga JI (3) Hussein O (4) Tanaka A (5) Shichijo T (6) Izaki M (7) Okamoto Y (8) Komohara Y (9) Matsuoka M

Cancer immunology research

Watanabe et al. analyzed ATL cells and cells infected with the ATL-causing HTLV-1, and identified a small number (<5% on average) of cells expressing DC-associated molecules (CD14, CD1c, CD11b, CD11c, and CD141), despite being derived from T cells. In a patient with ATL who entered remission after contracting COVID-19, these DC-like T cells increased, along with CTL responses to the HTLV-1 antigen Tax, suggesting these cells may contribute to antigen presentation and spontaneous regression. In an ATL cell line endogenously expressing BATF3, enforced expression of IRF8 and PU.1 increased CD86 expression and peptide presentation of Tax.

Contributed by Lauren Hitchings

(1) Watanabe M (2) Yasunaga JI (3) Hussein O (4) Tanaka A (5) Shichijo T (6) Izaki M (7) Okamoto Y (8) Komohara Y (9) Matsuoka M

Cancer immunology research

Watanabe et al. analyzed ATL cells and cells infected with the ATL-causing HTLV-1, and identified a small number (<5% on average) of cells expressing DC-associated molecules (CD14, CD1c, CD11b, CD11c, and CD141), despite being derived from T cells. In a patient with ATL who entered remission after contracting COVID-19, these DC-like T cells increased, along with CTL responses to the HTLV-1 antigen Tax, suggesting these cells may contribute to antigen presentation and spontaneous regression. In an ATL cell line endogenously expressing BATF3, enforced expression of IRF8 and PU.1 increased CD86 expression and peptide presentation of Tax.

Contributed by Lauren Hitchings

ABSTRACT: Spontaneous remission in patients with various cancers has been reported. Some patients with adult T-cell leukemia-lymphoma (ATL), have experienced spontaneous remission, although mechanisms for this remain unknown. In this study, we analyzed ATL cells and human T-cell leukemia virus type 1 (HTLV-1) infected cells using Cytometry by Time-Of-Flight mass spectrometry (CyTOF). We observed a small number (less than 5% on average) of ATL cells and HTLV-1 infected cells expressed CD14 and other dendritic cell (DC) associated molecules such as CD1c, CD11b, CD11c, and CD141. Single cell analysis revealed that these T cells expressing DC markers also contained rearranged TCR genes, indicating that these cells are indeed derived from T cells. In an ATL patient who entered into remission after contracting coronavirus disease 2019 (COVID-19), the number of DC-like T cells increased, and ELISPOT assay detected CTLs against Tax in accordance with regression of ATL. These findings suggest that DC-like ATL cells acquire antigen-presenting capability, and induce spontaneous remission through enhanced immunity to the virus. Specifically, in an ATL cell line, enforced expression of IRF8 and PU.1 in addition to endogenous BATF3 expression increased CD86 expression and enabled the cells to present Tax peptide antigens to T cells. Collectively, these data indicate that ATL cells acquire antigen-presenting activity when IRF8, PU.1 and BATF3 are expressed, suggesting that transition of a subset of T cells to DC-like T cells can induce immune responses to viral antigens, resulting in spontaneous remission. Thus, the transition of T cells to DC-like T cells is a unique mechanism for spontaneous remission in ATL.

Author Info: (1) Kumamoto University School of Medicine, Kumamoto, Japan. (2) Kumamoto University School of Medicine, Kumamoto, Japan. (3) Kumamoto University School of Medicine, Kumamoto, Japa

Author Info: (1) Kumamoto University School of Medicine, Kumamoto, Japan. (2) Kumamoto University School of Medicine, Kumamoto, Japan. (3) Kumamoto University School of Medicine, Kumamoto, Japan. (4) Kyoto University, Kyoto, Japan. (5) Kumamoto University School of Medicine, Kumamoto, Japan. (6) Kumamoto University, Kumamoto, Japan. (7) Kumamoto University, Kumamoto, Japan. (8) Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. (9) Kumamoto University, Kumamoto, Japan.

Citation: Cancer Immunol Res 2025 Apr 22 Epub04/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40261985

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CD22 CAR-T cells secreting CD19 T-cell engagers for improved control of B-cell acute lymphoblastic leukemia progression Spotlight 

(1) Arroyo-Ródenas J (2) Falgas A (3) Díez-Alonso L (4) Martinez-Moreno A (5) Roca-Ho H (6) Gil-Etayo FJ (7) Pérez-Pons A (8) Aguilar-Sopeña O (9) Velasco-Sidro M (10) Gómez-Rosel M (11) Jiménez-Matías B (12) Muñoz-Sánchez G (13) Pacheco Y (14) Bravo-Martín C (15) Ramírez-Fernández A (16) Jiménez-Reinoso A (17) González-Navarro EA (18) Juan M (19) Orfao A (20) Blanco B (21) Roda-Navarro P (22) Bueno C (23) Menéndez P (24) Alvarez-Vallina L

Journal for immunotherapy of cancer | Free PMC Article

To minimize tumor antigen loss and reduce the risk of CD19+ leukemia progression in r/r B-ALL, Arroyo-Ródenas ‍and Falgas et al. developed dual-targeted CD22 CAR T cells secreting an anti-CD19 T cell-engaging antibody (CAR-STAb-T). Compared to other validated dual CD19/22-targeted therapies (single-tandem TAN-CAR and pooled CAR-Ts), CAR-STAb-T cells recruited bystander non-transduced T cells efficiently at limiting E:T ratios, resulting in more potent and rapid cytotoxicity of B-ALL cells in long- and short-term cultures, and better leukemia control in a heterogeneous B cell model and in PDX mouse models under limiting T cell conditions. 

Contributed by Katherine Turner

(1) Arroyo-Ródenas J (2) Falgas A (3) Díez-Alonso L (4) Martinez-Moreno A (5) Roca-Ho H (6) Gil-Etayo FJ (7) Pérez-Pons A (8) Aguilar-Sopeña O (9) Velasco-Sidro M (10) Gómez-Rosel M (11) Jiménez-Matías B (12) Muñoz-Sánchez G (13) Pacheco Y (14) Bravo-Martín C (15) Ramírez-Fernández A (16) Jiménez-Reinoso A (17) González-Navarro EA (18) Juan M (19) Orfao A (20) Blanco B (21) Roda-Navarro P (22) Bueno C (23) Menéndez P (24) Alvarez-Vallina L

Journal for immunotherapy of cancer | Free PMC Article

To minimize tumor antigen loss and reduce the risk of CD19+ leukemia progression in r/r B-ALL, Arroyo-Ródenas ‍and Falgas et al. developed dual-targeted CD22 CAR T cells secreting an anti-CD19 T cell-engaging antibody (CAR-STAb-T). Compared to other validated dual CD19/22-targeted therapies (single-tandem TAN-CAR and pooled CAR-Ts), CAR-STAb-T cells recruited bystander non-transduced T cells efficiently at limiting E:T ratios, resulting in more potent and rapid cytotoxicity of B-ALL cells in long- and short-term cultures, and better leukemia control in a heterogeneous B cell model and in PDX mouse models under limiting T cell conditions. 

Contributed by Katherine Turner

BACKGROUND: CD19-directed cancer immunotherapies, based on engineered T cells bearing chimeric antigen receptors (CARs, CAR-T cells) or the systemic administration of bispecific T cell-engaging (TCE) antibodies, have shown impressive clinical responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, more than half of patients relapse after CAR-T or TCE therapy, with antigen escape or lineage switching accounting for one-third of disease recurrences. To minimize tumor escape, dual-targeting CAR-T cell therapies simultaneously targeting CD19 and CD22 have been developed and validated both preclinically and clinically. METHODS: We have generated the first dual-targeting strategy for B-cell malignancies based on CD22 CAR-T cells secreting an anti-CD19 TCE antibody (CAR-STAb-T) and conducted a comprehensive preclinical characterization comparing its therapeutic potential in B-ALL with that of previously validated dual-targeting CD19/CD22 tandem CAR cells (TanCAR-T cells) and co-administration of two single-targeting CD19 and CD22 CAR-T cells (pooled CAR-T cells). RESULTS: We demonstrate that CAR-STAb-T cells efficiently redirect bystander T cells, resulting in higher cytotoxicity of B-ALL cells than dual-targeting CAR-T cells at limiting effector:target ratios. Furthermore, when antigen loss was replicated in a heterogeneous B-ALL cell model, CAR-STAb T cells induced more potent and effective cytotoxic responses than dual-targeting CAR-T cells in both short- and long-term co-culture assays, reducing the risk of CD19-positive leukemia escape. In vivo, CAR-STAb-T cells also controlled leukemia progression more efficiently than dual-targeting CAR-T cells in patient-derived xenograft mouse models under T cell-limiting conditions. CONCLUSIONS: CD22 CAR-T cells secreting CD19 T-cell engagers show an enhanced control of B-ALL progression compared with CD19/CD22 dual CAR-based therapies, supporting their potential for clinical testing.

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investig

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (2) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (3) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (4) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (5) Josep Carreras Leukaemia Research Institute, Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. (6) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. (7) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain. Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain. (8) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (9) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (10) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (11) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. (12) Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (13) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (14) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (15) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (16) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (17) Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (18) Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Servicio de Inmunolog’a, Hospital Cl’nic de Barcelona, Barcelona, Spain. (19) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca, Salamanca, Spain. Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain. (20) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. (21) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (i+12), Madrid, Spain. (22) Josep Carreras Leukaemia Research Institute, Barcelona, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. (23) Josep Carreras Leukaemia Research Institute, Barcelona, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC; CB16/12/00400), Instituto de Salud Carlos III, Madrid, Spain. Instituci— Catalana de Recerca i Estudis Avanats (ICREA), Barcelona, Spain. Department of Biomedicine, School of Medicine, Universitat de Barcelona, Barcelona, Spain. Institut de Recerca Hospital Sant Joan de DŽu-Pediatric Cancer Center Barcelona (SJD-PCCB), Barcelona, Spain. (24) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain lalvarezv@ext.cnio.es cbueno@carrerasresearch.org pmenendez@carrerasresearch.org. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. CNIO-HMRIB Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Hospital del Mar Research Institute Barcelona (HMRIB), Madrid/Barcelona, Spain. Banc de Sang i Teixits (BST), Barcelona, Spain.

Citation: J Immunother Cancer 2025 Apr 30 13: Epub04/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40306957

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T-bet+CD8+ T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers

Spotlight 

(1) Tang S (2) Che X (3) Wang J (4) Li C (5) He X (6) Hou K (7) Zhang X (8) Guo J (9) Yang B (10) Li D (11) Cao L (12) Qu X (13) Wang Z (14) Liu Y

Nature communications | Free PMC Article

Tang, Che et al. utilized semi-supervised learning to stratify potential ICI responders among patients with microsatellite-stable gastric cancers (MSS GCs). The abundance of T-bet+ CD8+ T cells correlated with response to ICI treatment (AUC of 0.8), and there was a strong association with PIK3CA mutation and 9p24 amplification as well. IFNγ signaling pathway and CXCL9/10/11–CXCR3 chemotaxis pair-mediated spatial organizations of T-bet+ T cells and PD-L1+ tumor cell niches determined the sensitivity to ICI. Adoptive transfer of T-bet+ CD8+ T cells reinvigorated tumor immune microenvironments and sensitized immune-ignorant tumors to ICIs in humanized mouse models.

Contributed by Shishir Pant

(1) Tang S (2) Che X (3) Wang J (4) Li C (5) He X (6) Hou K (7) Zhang X (8) Guo J (9) Yang B (10) Li D (11) Cao L (12) Qu X (13) Wang Z (14) Liu Y

Nature communications | Free PMC Article

Tang, Che et al. utilized semi-supervised learning to stratify potential ICI responders among patients with microsatellite-stable gastric cancers (MSS GCs). The abundance of T-bet+ CD8+ T cells correlated with response to ICI treatment (AUC of 0.8), and there was a strong association with PIK3CA mutation and 9p24 amplification as well. IFNγ signaling pathway and CXCL9/10/11–CXCR3 chemotaxis pair-mediated spatial organizations of T-bet+ T cells and PD-L1+ tumor cell niches determined the sensitivity to ICI. Adoptive transfer of T-bet+ CD8+ T cells reinvigorated tumor immune microenvironments and sensitized immune-ignorant tumors to ICIs in humanized mouse models.

Contributed by Shishir Pant

ABSTRACT: More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8_+_T cell infiltration in their tumor compartments. T-bet+ CD8_+_T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8_+_T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.

Author Info: (1) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Bioth

Author Info: (1) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (2) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (3) Department of Immunology, College of Basic Medical Sciences, China Medical University, No. 77, Puhe Road, Shenyang, Liaoning, China. (4) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (5) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (6) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (7) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (8) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (9) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (10) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (11) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. (12) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. xjqu@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. xjqu@cmu.edu.cn. (13) Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, No.155, Nanjing Street, Shenyang, Liaoning, China. znwang@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, China Medical University, Shenyang, Liaoning, China. znwang@cmu.edu.cn. Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China. znwang@cmu.edu.cn. (14) Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China. ypliu@cmu.edu.cn. Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China. ypliu@cmu.edu.cn. Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China. ypliu@cmu.edu.cn. Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China. ypliu@cmu.edu.cn.

Citation: Nat Commun 2025 Apr 25 16:3905 Epub04/25/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40280928

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CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation Spotlight 

(1) Chen S (2) Wang Y (3) Dang J (4) Song N (5) Chen X (6) Wang J (7) Huang GN (8) Brown CE (9) Yu J (10) Weissman IL (11) Rosen ST (12) Feng M

Nature communications | Free PMC Article

Chen et al. demonstrated that an enhanced synthetic phagocytosis receptor (eSPR), which integrated FcRγ-driven phagocytic chimeric antigen receptors (CARs) with built-in secreted CD47 blockers, activated both the innate and adaptive immune systems to mount effective antitumor immune response and overcome tumor antigen heterogeneity. The eSPR macrophages showed a proinflammatory phenotype, rejected tumor repolarization, instilled pro-inflammatory traits into the TIME, and cross-presented antigens to T cells to elicit durable tumor control. The eSPR system functionality was further validated in ex vivo-differentiated primary human macrophages.

Contributed by Shishir Pant

(1) Chen S (2) Wang Y (3) Dang J (4) Song N (5) Chen X (6) Wang J (7) Huang GN (8) Brown CE (9) Yu J (10) Weissman IL (11) Rosen ST (12) Feng M

Nature communications | Free PMC Article

Chen et al. demonstrated that an enhanced synthetic phagocytosis receptor (eSPR), which integrated FcRγ-driven phagocytic chimeric antigen receptors (CARs) with built-in secreted CD47 blockers, activated both the innate and adaptive immune systems to mount effective antitumor immune response and overcome tumor antigen heterogeneity. The eSPR macrophages showed a proinflammatory phenotype, rejected tumor repolarization, instilled pro-inflammatory traits into the TIME, and cross-presented antigens to T cells to elicit durable tumor control. The eSPR system functionality was further validated in ex vivo-differentiated primary human macrophages.

Contributed by Shishir Pant

ABSTRACT: Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcR_-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.

Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) City of Hope National Medical Center, Duarte, CA, USA. (3) Department of Immuno-On

Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) City of Hope National Medical Center, Duarte, CA, USA. (3) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (4) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (5) Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (6) Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA. (7) Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA. Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. (8) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (9) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. City of Hope National Medical Center, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA, USA. (10) Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA, USA. Department of Pathology, Stanford Medicine, Stanford, CA, USA. (11) City of Hope National Medical Center, Duarte, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. Beckman Research Institute, City of Hope, Duarte, CA, USA. (12) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. mfeng@coh.org.

Citation: Nat Commun 2025 Apr 30 16:4069 Epub04/30/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40307254

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Cancer vaccine from intracellularly gelated tumor cells functionalized with CD47 blockage and damage-associated molecular pattern exposure Featured  

(1) Gao C (2) Luo R (3) Kwong CHT (4) Liu J (5) Tang M (6) Xie B (7) Duan T (8) Wang R

Cell reports. Medicine

Gao, Luo, Kwong, and Liu et al. developed an Intracellular hydrogelation process for inactivating whole tumor cells while leaving their morphology and tumor antigens intact for use as vaccines. Pre-treatment of the live tumor cells with doxorubicin (to induce increase “eat me” signals) and anti-CD47 (to block “don’t eat me” signals) prior to hydrogelation enhanced their immunogenicity. In vivo, hydrogelated whole tumor cell vaccines polarized CD4+ T cells toward a Th1 phenotype, reduced Tregs, limited T cell exhaustion, and elicited robust tumor antigen-specific T cell responses, resulting in enhanced tumor clearance and mouse survival. They also showed synergy with anti-PD-L1.

(1) Gao C (2) Luo R (3) Kwong CHT (4) Liu J (5) Tang M (6) Xie B (7) Duan T (8) Wang R

Cell reports. Medicine

Gao, Luo, Kwong, and Liu et al. developed an Intracellular hydrogelation process for inactivating whole tumor cells while leaving their morphology and tumor antigens intact for use as vaccines. Pre-treatment of the live tumor cells with doxorubicin (to induce increase “eat me” signals) and anti-CD47 (to block “don’t eat me” signals) prior to hydrogelation enhanced their immunogenicity. In vivo, hydrogelated whole tumor cell vaccines polarized CD4+ T cells toward a Th1 phenotype, reduced Tregs, limited T cell exhaustion, and elicited robust tumor antigen-specific T cell responses, resulting in enhanced tumor clearance and mouse survival. They also showed synergy with anti-PD-L1.

ABSTRACT: The effectiveness of whole tumor cell vaccines prepared by traditional inactivation methodology is often hindered by insufficient immunogenicity. Here, we report development of a cancer vaccine through the intracellular gelation of tumor cells, combined with CD47 blockade and damage-associated molecular pattern (DAMP) exposure, for effective tumor prevention and treatment. Intracellular hydrogelation preserves the morphology and antigenicity of tumor cells. CD47 blockade and DAMP exposure synergistically enhance the "eat me" signals and inhibit the "don't eat me" signals on tumor cells, significantly improving their immunogenicity. In the context of tumor prevention and treatment of pre-existing tumors, this vaccine polarizes CD4(+) T cells toward a T(H)1 phenotype, reduces regulatory T cells and T cell exhaustion, and elicits a robust tumor-antigen-specific T cell response. When combined with an immune checkpoint inhibitor, this vaccine demonstrates enhanced efficacy in eradicating established tumors. The successful application of this vaccine using ascites and subcutaneous tumor cells supports the feasibility of developing personalized whole tumor cell vaccines for diverse tumor types.

Author Info: (1) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Maca

Author Info: (1) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. (2) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. (3) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. (4) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. (5) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. (6) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. Electronic address: beibeixie@um.edu.mo. (7) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. (8) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. Electronic address: rwang@um.edu.mo.

Citation: Cell Rep Med 2025 Apr 29 102092 Epub04/29/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40345180

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Lung Cancer-Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-Dependent CD8+ T-cell Exclusion Spotlight 

(1) Torres-Mejia E (2) Weng S (3) Whittaker CA (4) Nguyen KB (5) Duong E (6) Yim L (7) Spranger S

Cancer immunology research | Free PMC Article

Torres-Mejia et al. showed that tumor cell-intrinsic SOX2 expression correlated with low T cell infiltration in NSCLC. Overexpression of SOX2 in tumor cells induced CD8+ T cell exclusion from the tumor core, and promoted tumor growth and resistance to anti-PD-1 and anti-CTLA-4 in the KP lung tumor model. SOX2 signaling upregulated CCL2 in tumor cells, resulting in increased recruitment of Tregs, which suppressed tumor vasculature, leading to CD8+ T cell exclusion from the tumor core. Anti-GITR treatment reduced Treg density within the TME, improved CD8+ T cell infiltration, and suppressed tumor growth when combined with checkpoint blockade.

Contributed by Shishir Pant

(1) Torres-Mejia E (2) Weng S (3) Whittaker CA (4) Nguyen KB (5) Duong E (6) Yim L (7) Spranger S

Cancer immunology research | Free PMC Article

Torres-Mejia et al. showed that tumor cell-intrinsic SOX2 expression correlated with low T cell infiltration in NSCLC. Overexpression of SOX2 in tumor cells induced CD8+ T cell exclusion from the tumor core, and promoted tumor growth and resistance to anti-PD-1 and anti-CTLA-4 in the KP lung tumor model. SOX2 signaling upregulated CCL2 in tumor cells, resulting in increased recruitment of Tregs, which suppressed tumor vasculature, leading to CD8+ T cell exclusion from the tumor core. Anti-GITR treatment reduced Treg density within the TME, improved CD8+ T cell infiltration, and suppressed tumor growth when combined with checkpoint blockade.

Contributed by Shishir Pant

ABSTRACT: Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration, creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. In this study, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs.

Author Info: (1) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (2) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Wellesley Coll

Author Info: (1) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (2) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Wellesley College, Wellesley, Massachusetts. (3) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (4) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. (5) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. (6) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (7) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts.

Citation: Cancer Immunol Res 2025 Apr 2 13:496-516 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39745382

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Antitumor CD4+ T Helper 1 Cells Target and Control the Outgrowth of Disseminated Cancer Cells Spotlight 

(1) Ramamoorthi G (2) Lee MC (3) Farrell CM (4) Snyder C (5) Garg SK (6) Aldrich AL (7) Lok V (8) Dominguez-Viqueira W (9) Olson-Mcpeek SK (10) Rosa M (11) Gautam N (12) Pilon-Thomas S (13) Cen L (14) Kodumudi KN (15) Wiener D (16) Oskarsson T (17) Gomes AP (18) Gatenby RA (19) Czerniecki BJ

Cancer immunology research | Free PMC Article

Ramamoorthi et al. demonstrated that disseminated cancer cells (DCCs) in bone marrow exhibited a different gene expression profile (stemness and EMT) than primary and metastatic tumor cells in breast cancer. Intratumorally delivered cDC1s primed tumor antigen-specific CD4+ Th1 cells, which modestly controlled primary tumor growth, but were able to migrate into distant organs to eradicate DCC-driven metastases. The CD4+ Th1 cytokine IFNγ regulated cancer stemness, EMT, cell cycle, and cholesterol biosynthesis signatures to restrain the tumorigenic potential of DCCs, but failed to eradicate DCC-driven metastases in IFNγ KO mice.

Contributed by Shishir Pant

(1) Ramamoorthi G (2) Lee MC (3) Farrell CM (4) Snyder C (5) Garg SK (6) Aldrich AL (7) Lok V (8) Dominguez-Viqueira W (9) Olson-Mcpeek SK (10) Rosa M (11) Gautam N (12) Pilon-Thomas S (13) Cen L (14) Kodumudi KN (15) Wiener D (16) Oskarsson T (17) Gomes AP (18) Gatenby RA (19) Czerniecki BJ

Cancer immunology research | Free PMC Article

Ramamoorthi et al. demonstrated that disseminated cancer cells (DCCs) in bone marrow exhibited a different gene expression profile (stemness and EMT) than primary and metastatic tumor cells in breast cancer. Intratumorally delivered cDC1s primed tumor antigen-specific CD4+ Th1 cells, which modestly controlled primary tumor growth, but were able to migrate into distant organs to eradicate DCC-driven metastases. The CD4+ Th1 cytokine IFNγ regulated cancer stemness, EMT, cell cycle, and cholesterol biosynthesis signatures to restrain the tumorigenic potential of DCCs, but failed to eradicate DCC-driven metastases in IFNγ KO mice.

Contributed by Shishir Pant

ABSTRACT: Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen-specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1- T cells, supporting their nonexhaustion stage. Phenotypic characterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor-draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7-CXCR3+ Th1 cells into distant organs further revealed their potential role in eradicating DCC-driven metastasis. The intratumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4- or IFN-_ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-_ production, inhibited various molecular aspects and increased classical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metastasis in patients.

Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast

Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (4) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (5) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (6) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (7) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (8) Small Animal Imaging Laboratory Core, Moffitt Cancer Center, Tampa, Florida. (9) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (10) Department of Pathology, Moffitt Cancer Center, Tampa, Florida. (11) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (12) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (13) Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. (14) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (15) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (16) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (17) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (18) Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida. (19) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida.

Citation: Cancer Immunol Res 2025 May 2 13:729-748 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40249209

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Targeting cancer-associated glycosylation for adoptive T cell therapy of solid tumors Spotlight 

(1) Zingg A (2) Ritschard R (3) Thut H (4) Buchi M (5) Holbro A (6) Oseledchyk A (7) Heinzelmann V (8) Buser A (9) Binder M (10) Zippelius A (11) Rodrigues Mantuano N (12) Matter M (13) LŠubli H

Cancer immunology research

Based on the highly specific 2G12-2B2 antibody, Zingg et al. generated a fully human CAR targeting sialyl-Thomsen-Nouveau antigen (STn), which was expressed at high levels in colon, pancreatic, and gynecological cancers compared to healthy tissues. In vitro, CAR T cells with CD28 and 4-1BB costimulatory domains, but not TRuC constructs, were cytotoxic over longer periods of time, even at low effector:target cell ratios or at native antigen expression levels. In mice, CAR T cells with CD28 showed increased tumor infiltration and induced long-term tumor control and some cures, without considerable toxicity, despite some luminal expression of STn in healthy gastrointestinal tissues.

Contributed by Lauren Hitchings

(1) Zingg A (2) Ritschard R (3) Thut H (4) Buchi M (5) Holbro A (6) Oseledchyk A (7) Heinzelmann V (8) Buser A (9) Binder M (10) Zippelius A (11) Rodrigues Mantuano N (12) Matter M (13) LŠubli H

Cancer immunology research

Based on the highly specific 2G12-2B2 antibody, Zingg et al. generated a fully human CAR targeting sialyl-Thomsen-Nouveau antigen (STn), which was expressed at high levels in colon, pancreatic, and gynecological cancers compared to healthy tissues. In vitro, CAR T cells with CD28 and 4-1BB costimulatory domains, but not TRuC constructs, were cytotoxic over longer periods of time, even at low effector:target cell ratios or at native antigen expression levels. In mice, CAR T cells with CD28 showed increased tumor infiltration and induced long-term tumor control and some cures, without considerable toxicity, despite some luminal expression of STn in healthy gastrointestinal tissues.

Contributed by Lauren Hitchings

ABSTRACT: CAR T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen - the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn) - was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials.

Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedic

Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedicine, University of Basel, Switzerland. (5) University of Basel, Basel, Switzerland. (6) University of Basel, Basel, Switzerland. (7) University Hospital of Basel, Basel, Switzerland. (8) University of Basel, Basel, Switzerland. (9) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. (10) University Hospital of Basel, Basel, Switzerland. (11) University of Basel, Basel, Switzerland. (12) University Hospital of Basel, Switzerland. (13) University of Basel, Basel, Switzerland.

Citation: Cancer Immunol Res 2025 Apr 16 Epub04/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40237717

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