Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models
(1) Afratis NA (2) Parikh S (3) Adir I (4) Parikh R (5) Solomonov I (6) Kollet O (7) Gelb S (8) Sade Y (9) Vaknine H (10) Zemser-Werner V (11) Brener R (12) Nizri E (13) Hershkovitz D (14) Ricard-Blum S (15) Levy C (16) Sagi I
Dendritic cell progenitors engineered to express extracellular-vesicle-internalizing receptors enhance cancer immunotherapy in mouse models
(1) Ghasemi A (2) Martinez-Usatorre A (3) Liu Y (4) Demagny H (5) Li L (6) Mohammadzadeh Y (7) Hurtado A (8) Hicham M (9) Henneman L (10) Pritchard CEJ (11) Speiser DE (12) Migliorini D (13) De Palma M
(1) Ghasemi A (2) Martinez-Usatorre A (3) Liu Y (4) Demagny H (5) Li L (6) Mohammadzadeh Y (7) Hurtado A (8) Hicham M (9) Henneman L (10) Pritchard CEJ (11) Speiser DE (12) Migliorini D (13) De Palma M
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (2) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (3) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (4) Laboratory of Metabolic Signaling, Institute of Bioengineering, EPFL, Lausanne, Switzerland. (5) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (6) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (7) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (8) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (9) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (10) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (11) Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (12) Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. Department of Oncology, Geneva University Hospital (HUG), Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva (UNIGE), Geneva, Switzerland. (13) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. michele.depalma@epfl.ch. Agora Cancer Research Center, Lausanne, Switzerland. michele.depalma@epfl.ch. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. michele.depalma@epfl.ch.
Citation: Nat Commun 2025 Oct 15 16:9148 Epub10/15/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41093860
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A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice
(1) Cao W (2) Chen J (3) Fu Y (4) Jiang H (5) Gao Y (6) Huang H (7) Fu YX (8) Wang W
(1) Cao W (2) Chen J (3) Fu Y (4) Jiang H (5) Gao Y (6) Huang H (7) Fu YX (8) Wang W
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijin
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (7) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Changping District, Beijing, China. yangxinfu@tsinghua.edu.cn. (8) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn.
Citation: Nat Commun 2025 Oct 10 16:9029 Epub10/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41073424
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IL-2/IL-15 signaling induces NK cell production of FLT3LG augmenting anti-PD-1 immunotherapy
(1) Avanessian SC (2) van den Bijgaart RJE (3) Chew NW (4) Supper VM (5) Tang TT (6) Zhang Y (7) Zhao YQ (8) Abe K (9) Gauthier J (10) Barry KC
(1) Avanessian SC (2) van den Bijgaart RJE (3) Chew NW (4) Supper VM (5) Tang TT (6) Zhang Y (7) Zhao YQ (8) Abe K (9) Gauthier J (10) Barry KC
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (5) Fred Hutchinson Cancer Center, Seattle, WA, United States. (6) Fred Hutchinson Cancer Center, Seattle, United States. (7) Fred Hutchinson Cancer Center, United States. (8) Fred Hutchinson Cancer Center, Seattle, WA, United States. (9) Fred Hutchinson Cancer Center, Seattle, France. (10) Fred Hutchinson Cancer Center, Seattle, WA, United States.
Citation: Cancer Immunol Res 2025 Oct 13 Epub10/13/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41081432
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Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia
(1) Sandn C (2) Landberg N (3) Pea-Martnez P (4) Thorsson H (5) Daga S (6) Puente-Moncada N (7) Rodriguez-Zabala M (8) von Palffy S (9) Rissler M (10) Lazarevic V (11) Juliusson G (12) Ohlin M (13) Hyrenius-Wittsten A (14) Orsmark-Pietras C (15) Lilljebjrn H (16) gerstam H (17) Fioretos T
(1) Sandn C (2) Landberg N (3) Pea-Martnez P (4) Thorsson H (5) Daga S (6) Puente-Moncada N (7) Rodriguez-Zabala M (8) von Palffy S (9) Rissler M (10) Lazarevic V (11) Juliusson G (12) Ohlin M (13) Hyrenius-Wittsten A (14) Orsmark-Pietras C (15) Lilljebjrn H (16) gerstam H (17) Fioretos T
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laborat
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (3) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (4) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (5) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (6) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (7) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (8) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (9) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (10) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (11) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (12) Department of Immunotechnology, Lund University, Lund, Sweden. SciLifeLab Drug Discovery and Development Platform, Lund University, Lund, Sweden. (13) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (14) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (15) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (16) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (17) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. thoas.fioretos@med.lu.se. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. thoas.fioretos@med.lu.se.
Citation: Nat Cancer 2025 Oct 3 Epub10/03/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41044242
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Local delivery of IL-15 and anti-PD-L1 nanobody by in vitro-transcribed circILNb elicits superior antitumor immunity in cold tumors
(1) Niu D (2) Ma X (3) Zhu J (4) Sun L (5) Zhang S (6) Wu Y (7) Shan M (8) Dai X (9) Liao Y (10) Liu D (11) Lu L (12) Yang M (13) Zou Q (14) Lian J
(1) Niu D (2) Ma X (3) Zhu J (4) Sun L (5) Zhang S (6) Wu Y (7) Shan M (8) Dai X (9) Liao Y (10) Liu D (11) Lu L (12) Yang M (13) Zou Q (14) Lian J
Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Fac
Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (3) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (4) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (5) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (6) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (7) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (8) College of Education and Science, Chongqing Normal University, Chongqing 400047, China. (9) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (10) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (11) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (12) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: yangmingzhen0807@126.com. (13) National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: qmzou2007@163.com. (14) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.
Citation: Cell Rep Med 2025 Oct 10 102413 Epub10/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41075789
CRATER tumor niches facilitate CD8+ T cell engagement and correspond with immunotherapy success
(1) Ludin A (2) Stirtz GL (3) Tal A (4) Nirmal AJ (5) Pfaff KL (6) Manos M (7) Besson N (8) Eskndir N (9) Porter B (10) Jones SM (11) Faulkner HM (12) Gong Q (13) Liu S (14) Barrera I (15) Wu L (16) Pessoa Rodrigues C (17) Sahu A (18) Jerison E (19) Alessi JV (20) Ricciuti B (21) Richardson DS (22) Weiss JD (23) Moreau HM (24) Stanhope ME (25) Afeyan AB (26) Sefton J (27) McCall WD (28) Formato E (29) Yang S (30) Zhou Y (31) Hoytema van Konijnenburg DP (32) Cole HL (33) Cordova M (34) Deng L (35) Rajadhyaksha M (36) Quake SR (37) Awad MM (38) Chen F (39) Wucherpfennig KW (40) Sorger PK (41) Hodi FS (42) Rodig SJ (43) Murphy GF (44) Zon LI
(1) Ludin A (2) Stirtz GL (3) Tal A (4) Nirmal AJ (5) Pfaff KL (6) Manos M (7) Besson N (8) Eskndir N (9) Porter B (10) Jones SM (11) Faulkner HM (12) Gong Q (13) Liu S (14) Barrera I (15) Wu L (16) Pessoa Rodrigues C (17) Sahu A (18) Jerison E (19) Alessi JV (20) Ricciuti B (21) Richardson DS (22) Weiss JD (23) Moreau HM (24) Stanhope ME (25) Afeyan AB (26) Sefton J (27) McCall WD (28) Formato E (29) Yang S (30) Zhou Y (31) Hoytema van Konijnenburg DP (32) Cole HL (33) Cordova M (34) Deng L (35) Rajadhyaksha M (36) Quake SR (37) Awad MM (38) Chen F (39) Wucherpfennig KW (40) Sorger PK (41) Hodi FS (42) Rodig SJ (43) Murphy GF (44) Zon LI
ABSTRACT: T cell-mediated tumor killing underlies immunotherapy success. Here, we used long-term in vivo imaging and high-resolution spatial transcriptomics of zebrafish endogenous melanoma, as well as multiplex imaging of human melanoma, to identify domains facilitating the immune response during immunotherapy. We identified cancer regions of antigen presentation and T cell engagement and retention (CRATERs) as pockets at the stroma-melanocyte boundaries of zebrafish and human melanoma. CRATERs are rich in antigen-recognition molecules, harboring the highest density of CD8(+) T cells in tumors. In zebrafish, CD8(+) T cells formed prolonged interactions with melanoma cells within CRATERs, characteristic of antigen recognition. Following immunostimulatory treatment, CRATERs expanded, becoming the major sites of activated CD8(+) T cell accumulation and tumor killing. In humans, elevation in CRATER density in biopsies following immune checkpoint blockade (ICB) therapy correlated with a clinical response to therapy. CRATERs are structures that show active tumor killing and may be useful as a diagnostic indicator for immunotherapy success.
Author Info: (1) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Ho
Author Info: (1) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. (2) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (3) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (4) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. (5) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (6) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (7) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (8) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (9) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (10) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (11) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA. (15) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (16) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. (17) Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. (18) Department of Physics, University of Chicago, Chicago, IL 60637, USA. (19) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (20) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (21) Harvard Center for Biological Imaging, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA. (22) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (23) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (24) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (25) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (26) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (27) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (28) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. (29) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. (30) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. (31) Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. (32) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA. (33) Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. (34) Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. (35) Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. (36) Department of Bioengineering and Applied Sciences, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. (37) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (38) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA. (39) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (40) Ludwig Center at Harvard, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. (41) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Parker Institute for Cancer Immunotherapy, Boston, MA, USA. (42) Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (43) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (44) Harvard Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: leonard.zon@enders.tch.harvard.edu.
Citation: Cell 2025 Oct 17 Epub10/17/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41109214
Tags:
Primate resident memory T cells activate humoral and stromal immunity
(1) Joag V (2) Bimber BN (3) Quarnstrom CF (4) Bollimpelli VS (5) Schenkel JM (6) Fraser KA (7) Bertogliat M (8) Soerens AG (9) Stolley JM (10) O'Flanagan SD (11) Rosato PC (12) Gavil NV (13) Knzli M (14) Mitchell JS (15) Legere T (16) Jean S (17) Upadhyay AA (18) Kang CY (19) Gibbs J (20) Yewdell JW (21) Fife BT (22) Park H (23) Hansen SG (24) Bosinger SE (25) Barber GN (26) Skinner PJ (27) Vezys V (28) Hunter E (29) Picker LJ (30) Amara RR (31) Masopust D
Joag et al. demonstrated that systemic T cell-based vaccines generate robust T cell surveillance throughout the body, integrating cellular and humoral immunity. Intravenous heterologous prime-boost vaccination in macaques established SIV-gag–specific CD8⁺ memory (including resident memory [Trm]), T cells across more than 30 lymphoid, mucosal, and visceral tissues. Local Trm reactivation in the reproductive tract mucosa activated stromal, endothelial, and innate lymphoid cells, amplifying interferon-driven antiviral programs. These signals recruited CD4⁺ T cells with host-defense signatures, and mobilized B and plasma cells.
Contributed by Shishir Pant
(1) Joag V (2) Bimber BN (3) Quarnstrom CF (4) Bollimpelli VS (5) Schenkel JM (6) Fraser KA (7) Bertogliat M (8) Soerens AG (9) Stolley JM (10) O'Flanagan SD (11) Rosato PC (12) Gavil NV (13) Knzli M (14) Mitchell JS (15) Legere T (16) Jean S (17) Upadhyay AA (18) Kang CY (19) Gibbs J (20) Yewdell JW (21) Fife BT (22) Park H (23) Hansen SG (24) Bosinger SE (25) Barber GN (26) Skinner PJ (27) Vezys V (28) Hunter E (29) Picker LJ (30) Amara RR (31) Masopust D
Joag et al. demonstrated that systemic T cell-based vaccines generate robust T cell surveillance throughout the body, integrating cellular and humoral immunity. Intravenous heterologous prime-boost vaccination in macaques established SIV-gag–specific CD8⁺ memory (including resident memory [Trm]), T cells across more than 30 lymphoid, mucosal, and visceral tissues. Local Trm reactivation in the reproductive tract mucosa activated stromal, endothelial, and innate lymphoid cells, amplifying interferon-driven antiviral programs. These signals recruited CD4⁺ T cells with host-defense signatures, and mobilized B and plasma cells.
Contributed by Shishir Pant
ABSTRACT: CD8(+) resident memory T (Trm) cells comprise a small population of frontline sentinels compared with the large tissues they surveil, making outsized contributions to immune protection from infection. Here, we interrogated mechanisms of Trm cell function in primates. Intravenous immunization of macaques with a simian immunodeficiency virus (SIV)-gag-containing heterologous prime-boost-boost vaccine established memory T cells in >30 tissues, including visceral and mucosal compartments. Upon in vivo reactivation in the reproductive tract, antigen-sensing CD8(+) Trm activated local stromal, parenchymal, and innate and adaptive immune cells. Stromal and parenchymal cells accentuated leukocyte migration and antiviral defenses. B and plasma cells mobilized into the vaginal mucosa, and bloodborne CD4(+) T cells were recruited and adopted a host-defense program. Our findings demonstrate that systemic vaccination promotes a Trm cell response in barrier compartments and that Trm cells repurpose abundant neighboring stromal, parenchymal, and immune cells to amplify alarm signals and activate diverse host defenses.
Author Info: (1) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vineet.joag@seattlechildrens.org. (2)
Author Info: (1) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: vineet.joag@seattlechildrens.org. (2) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (3) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (4) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (5) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (6) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (7) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (8) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (9) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (10) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (11) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (12) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (13) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (14) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (15) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (16) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (17) Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. (18) Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON N6G 2V4, Canada. (19) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (20) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. (21) Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA. (22) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (23) Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA. (24) Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. (25) Center for Innate Immunity and Inflammation, Pelotonia Institute for Immuno-oncology, the James Comprehensive Cancer Center, Department of Surgery, Ohio State University, Columbus, OH, USA. (26) Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA. (27) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. (28) Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA. (29) Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA. (30) Department of Microbiology and Immunology, Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA 30322, USA. (31) Department of Microbiology and Immunology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: masopust@umn.edu.
Citation: Immunity 2025 Oct 14 58:2541-2555.e6 Epub
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41092897
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Anticancer immune responses are hindered by cis interaction of inhibitory checkpoint SIRPα
(1) Tang Z (2) Zhong MC (3) Qian J (4) Dou J (5) Wong LS (6) Li J (7) Galindo CC (8) Davidson D (9) Veillette A
Tang et al. showed that phagocytosis suppression by Signal Regulatory Protein α (SIRPα) depends not only on trans CD47 binding and phosphatase signaling, but also on cis interactions with CD18 (β2 integrin) on the macrophage surface. Distinct SIRPα residues interacted with CD18 and CD47. SIRPα–CD18 interaction prevented Mac-1 (αMβ2, CD18/CD11b) activation, which is required for phagocytosis in synergy with the SIRPα–CD47 interaction. In mouse tumor models, treatment with anti-SIRPα bispecific Abs blocking both CD47 and CD18 interactions caused a greater increase in phagocytosis and antitumor activity than monospecific anti-SIRPα Abs.
Contributed by Paula Hochman
(1) Tang Z (2) Zhong MC (3) Qian J (4) Dou J (5) Wong LS (6) Li J (7) Galindo CC (8) Davidson D (9) Veillette A
Tang et al. showed that phagocytosis suppression by Signal Regulatory Protein α (SIRPα) depends not only on trans CD47 binding and phosphatase signaling, but also on cis interactions with CD18 (β2 integrin) on the macrophage surface. Distinct SIRPα residues interacted with CD18 and CD47. SIRPα–CD18 interaction prevented Mac-1 (αMβ2, CD18/CD11b) activation, which is required for phagocytosis in synergy with the SIRPα–CD47 interaction. In mouse tumor models, treatment with anti-SIRPα bispecific Abs blocking both CD47 and CD18 interactions caused a greater increase in phagocytosis and antitumor activity than monospecific anti-SIRPα Abs.
Contributed by Paula Hochman
ABSTRACT: Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα's inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β2 integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau S
Author Info: (1) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China. (2) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (3) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (4) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (5) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (6) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. (7) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (8) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. (9) Laboratory of Molecular Oncology, Institut de recherches cliniques de Montral (IRCM), Montral, Canada. Department of Medicine, McGill University, Montral, Canada. Department of Medicine, University of Montral, Montral, Canada.
Citation: Sci Immunol 2025 Oct 17 10:eadv5085 Epub10/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41071905
Collagen-disrupting attIL12 TIL therapy boosts deep T cell infiltration via dual signaling activation and CCKAR reduction in sarcomas
(1) Hu J (2) Singh H (3) Jin Y (4) Zhang W (5) Wang J (6) Xia X (7) Somaiah N (8) Gorlick R (9) Li S
Across clinical sarcomas, collagen expression increased with tumor stage and associated with reduced patient survival. To treat ECM-rich tumors, Hu and Singh et al. modified TILs to express a cell-surface vimentin (CSV, sarcoma antigen)-targeting peptide linked to IL-12 (attIL12-TILs). Compared to standard TILs, attIL12-TILs improved IFNγ production, reduced tumor collagen expression, and boosted infiltration and tumor control in mouse sarcoma models. Inhibiting signaling by either TCRs or CSV abrogated these effects. Mechanistically, attIL12-TILs reduced tumor cell collagen levels via IFNγ inhibition of TGFβ-SMAD3 and CCKAR-pAKT pathways.
Contributed by Alex Najibi
(1) Hu J (2) Singh H (3) Jin Y (4) Zhang W (5) Wang J (6) Xia X (7) Somaiah N (8) Gorlick R (9) Li S
Across clinical sarcomas, collagen expression increased with tumor stage and associated with reduced patient survival. To treat ECM-rich tumors, Hu and Singh et al. modified TILs to express a cell-surface vimentin (CSV, sarcoma antigen)-targeting peptide linked to IL-12 (attIL12-TILs). Compared to standard TILs, attIL12-TILs improved IFNγ production, reduced tumor collagen expression, and boosted infiltration and tumor control in mouse sarcoma models. Inhibiting signaling by either TCRs or CSV abrogated these effects. Mechanistically, attIL12-TILs reduced tumor cell collagen levels via IFNγ inhibition of TGFβ-SMAD3 and CCKAR-pAKT pathways.
Contributed by Alex Najibi
ABSTRACT: Tumor-targeted T cell therapies of various types have been booming, but T cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell-surface vimentin (CSV)-targeted and membrane-anchored interleukin 12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, but fail to reduce collagen expression by tumor cells, resulting in resistance to attIL12-T cell treatment. In this study, we found that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells by attIL12-TILs overcomes resistance to attIL12-T cell treatment and required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and human leukocyte antigen-T cell receptor on attIL12-TILs; When either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells induced interferon gamma production synergistically, which in combination with CCKAR downregulation reduced collagen expression through suppression of both transforminggrowth factor beta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T cell infiltration and improved tumor growth inhibition in PDX sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T cell infiltration in high-grade, collagen-rich tumors.
Author Info: (1) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Division of Pediatrics, Department of Pedia
Author Info: (1) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (3) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (4) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (5) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (6) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (7) Division of Cancer Medicine, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (8) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (9) Division of Pediatrics, Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Citation: Proc Natl Acad Sci U S A 2025 Oct 14 122:e2507542122 Epub10/06/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41052334