Abstract
Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 973-988.e9 |
| Journal | Cancer Cell |
| Volume | 39 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 12 2021 |
Keywords
- CD8 T cells
- Tim-4
- cavity-resident macrophages
- immune checkpoint blockade
- immunotherapy
- peritoneal macrophages
- phosphatidylserine
- pleural macrophages
- scRNA-seq
- sequestration
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. / Chow, Andrew; Schad, Sara; Green, Michael D. et al.
In: Cancer Cell, Vol. 39, No. 7, 12.07.2021, p. 973-988.e9.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity
AU - Chow, Andrew
AU - Schad, Sara
AU - Green, Michael D.
AU - Hellmann, Matthew D.
AU - Allaj, Viola
AU - Ceglia, Nicholas
AU - Zago, Giulia
AU - Shah, Nisargbhai S.
AU - Sharma, Sai Kiran
AU - Mattar, Marissa
AU - Chan, Joseph
AU - Rizvi, Hira
AU - Zhong, Hong
AU - Liu, Cailian
AU - Bykov, Yonina
AU - Zamarin, Dmitriy
AU - Shi, Hongyu
AU - Budhu, Sadna
AU - Wohlhieter, Corrin
AU - Uddin, Fathema
AU - Gupta, Aditi
AU - Khodos, Inna
AU - Waninger, Jessica J.
AU - Qin, Angel
AU - Markowitz, Geoffrey J.
AU - Mittal, Vivek
AU - Balachandran, Vinod
AU - Durham, Jennifer N.
AU - Le, Dung T.
AU - Zou, Weiping
AU - Shah, Sohrab P.
AU - McPherson, Andrew
AU - Panageas, Katherine
AU - Lewis, Jason S.
AU - Perry, Justin S.A.
AU - de Stanchina, Elisa
AU - Sen, Triparna
AU - Poirier, John T.
AU - Wolchok, Jedd D.
AU - Rudin, Charles M.
AU - Merghoub, Taha
N1 - Funding Information: JDW is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, Elucida, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Linneaus, Maverick Therapeutics, Merck, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Trishula, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW has received grant/research support from Bristol Myers Squibb; Sephora. JDW has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. JDW is a co-inventor on patent applications related to heteroclitic cancer vaccines and recombinant poxviruses for cancer immunotherapy. JDW and TM are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). TM is a consultant for Immunos Therapeutics and Pfizer. TM is a cofounder of and equity holder in IMVAQ Therapeutics. TM receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. TM is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo and PharmaMar and is on the scientific advisory boards of Elucida, Bridge and Harpoon. Unrelated to this work, D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech; and personal/consultancy fees from Merck, Synlogic Therapeutics, GSK, Genentech, Xencor, Memgen, Immunos, CrownBio, and Agenus. D.Z. is an inventor on patents related to the use of Newcastle Disease Virus that has been licensed to Merck. MDH received research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, Syndax, as well as equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen and has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom. She has received speaking honoraria from Merck and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. SS is a shareholder of Canexia Health Inc. Funding Information: We are grateful for experimental support from the MSKCC Molecular Cytology Core Facility (in particular Drs. Anthony Santella and Afsar Barlas), the MSKCC Small Animal Imaging Core Facility, the MSKCC Flow Cytometry Core Facility, and the Integrated Genomics Core, which are funded by MSK's Cancer Center Support Grant/Core Grant (P30 CA008748). We are grateful to Maximiliano Meneses, Mariana Ward, Rebecca Landau, and Sean Guzman for their invaluable help in obtaining clinical biospecimens. We thank Dr. Shigekazu Nagata (Osaka University) for providing Tim-4 KO mice and for providing valuable feedback on our manuscript. We thank Clare Wilhelm for editing our manuscript. We are also grateful to other members of the Wolchok and Rudin laboratories for insightful discussions. This research was funded in part through the NIH NCI Cancer Center support grant P30 CA008748, NCI R01 CA056821, U01 CA199215, U24 CA213274, P01 CA129243, R01 CA197936, R35 CA232130, and K08 CA248723; the Ludwig Collaborative and Swim Across America Laboratory; the Emerald Foundation; the Parker Institute for Cancer Immunotherapy, MSKCC; the Department of Medicine, MSKCC; Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant (SU2C-AACR-DT17-15). A.C. was supported by an MSKCC Investigational Cancer Therapeutics Training Program fellowship (T32 CA-009207) and Clinical Investigator Award from the National Cancer Institute (K08 CA-248723). T.S. is supported by the Druckenmiller Center for Lung Cancer Research, Parker Institute for Cancer Immunotherapy (PICI) grant, International Association for the Study of Lung Cancer grant, and Department of Defense LCRP-IITRA. A.C. conceived the project, performed and analyzed the experiments, drafted the manuscript, and edited the manuscript with assistance from all authors. S.S. V.A. N.C. G.Z. N.S.S. S.K.S. H.Z. C.L. H.S. S.B. C.W. F.U. A.G. and I.K. performed and analyzed the experiments. M.D.G. M.D.H. M.M. J.C. H.R. Y.B. D.Z. J.J.W. A.Q. V.B. J.N.D. and D.T.L. provided assistance with retrospective clinical analyses, radiographic annotation, and biospecimen collection. W.Z. G.J.M. and V.M. provided critical reagents. K.P. provided biostatistical support for this manuscript. S.P.S. A.M. J.S.L. J.S.A.P. E.d.S. T.S. and J.T.P. supervised experiments. J.D.W. C.M.R. and T.M. conceived the project, supervised experiments, and edited the manuscript. JDW is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Arsenal IO, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, Elucida, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Linneaus, Maverick Therapeutics, Merck, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Trishula, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. JDW has received grant/research support from Bristol Myers Squibb; Sephora. JDW has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. JDW is a co-inventor on patent applications related to heteroclitic cancer vaccines and recombinant poxviruses for cancer immunotherapy. JDW and TM are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). TM is a consultant for Immunos Therapeutics and Pfizer. TM is a cofounder of and equity holder in IMVAQ Therapeutics. TM receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. TM is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus?based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo and PharmaMar and is on the scientific advisory boards of Elucida, Bridge and Harpoon. Unrelated to this work, D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech; and personal/consultancy fees from Merck, Synlogic Therapeutics, GSK, Genentech, Xencor, Memgen, Immunos, CrownBio, and Agenus. D.Z. is an inventor on patents related to the use of Newcastle Disease Virus that has been licensed to Merck. MDH received research grant from BMS; personal fees from Achilles, Arcus, AstraZeneca, Blueprint, BMS, Genentech/Roche, Genzyme, Immunai, Instil Bio, Janssen, Merck, Mirati, Natera, Nektar, Pact Pharma, Regeneron, Shattuck Labs, Syndax, as well as equity options from Arcus, Factorial, Immunai, and Shattuck Labs. A patent filed by MSKCC related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen and has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom. She has received speaking honoraria from Merck and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. SS is a shareholder of Canexia Health Inc. Funding Information: We are grateful for experimental support from the MSKCC Molecular Cytology Core Facility (in particular Drs. Anthony Santella and Afsar Barlas), the MSKCC Small Animal Imaging Core Facility, the MSKCC Flow Cytometry Core Facility, and the Integrated Genomics Core, which are funded by MSK’s Cancer Center Support Grant/Core Grant ( P30 CA008748 ). We are grateful to Maximiliano Meneses, Mariana Ward, Rebecca Landau, and Sean Guzman for their invaluable help in obtaining clinical biospecimens. We thank Dr. Shigekazu Nagata (Osaka University) for providing Tim-4 KO mice and for providing valuable feedback on our manuscript. We thank Clare Wilhelm for editing our manuscript. We are also grateful to other members of the Wolchok and Rudin laboratories for insightful discussions. This research was funded in part through the NIH NCI Cancer Center support grant P30 CA008748 , NCI R01 CA056821 , U01 CA199215 , U24 CA213274 , P01 CA129243 , R01 CA197936 , R35 CA232130 , and K08 CA248723 ; the Ludwig Collaborative and Swim Across America Laboratory; the Emerald Foundation; the Parker Institute for Cancer Immunotherapy, MSKCC; the Department of Medicine, MSKCC; Stand Up To Cancer (SU2C)- American Cancer Society Lung Cancer Dream Team Translational research grant ( SU2C-AACR-DT17-15 ). A.C. was supported by an MSKCC Investigational Cancer Therapeutics Training Program fellowship ( T32 CA-009207 ) and Clinical Investigator Award from the National Cancer Institute ( K08 CA-248723 ). T.S. is supported by the Druckenmiller Center for Lung Cancer Research, Parker Institute for Cancer Immunotherapy (PICI) grant, International Association for the Study of Lung Cancer grant, and Department of Defense LCRP-IITRA. Publisher Copyright: © 2021
PY - 2021/7/12
Y1 - 2021/7/12
N2 - Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments.
AB - Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments.
KW - CD8 T cells
KW - Tim-4
KW - cavity-resident macrophages
KW - immune checkpoint blockade
KW - immunotherapy
KW - peritoneal macrophages
KW - phosphatidylserine
KW - pleural macrophages
KW - scRNA-seq
KW - sequestration
UR - http://www.scopus.com/inward/record.url?scp=85109428361&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109428361&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2021.05.006
DO - 10.1016/j.ccell.2021.05.006
M3 - Article
C2 - 34115989
AN - SCOPUS:85109428361
VL - 39
SP - 973-988.e9
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 7
ER -