Abstract
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
| Original language | English |
|---|---|
| Pages (from-to) | 1561-1577.e7 |
| Journal | Immunity |
| Volume | 54 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 13 2021 |
Keywords
- CD36
- CD8 T cells
- lipid peroxidation
- oxidized lipids
- tumor microenvironment
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Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. / Xu, Shihao; Chaudhary, Omkar; Rodríguez-Morales, Patricia et al.
In: Immunity, Vol. 54, No. 7, 13.07.2021, p. 1561-1577.e7.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors
AU - Xu, Shihao
AU - Chaudhary, Omkar
AU - Rodríguez-Morales, Patricia
AU - Sun, Xiaoli
AU - Chen, Dan
AU - Zappasodi, Roberta
AU - Xu, Ziyan
AU - Pinto, Antonio F.M.
AU - Williams, April
AU - Schulze, Isabell
AU - Farsakoglu, Yagmur
AU - Varanasi, Siva Karthik
AU - Low, Jun Siong
AU - Tang, Wenxi
AU - Wang, Haiping
AU - McDonald, Bryan
AU - Tripple, Victoria
AU - Downes, Michael
AU - Evans, Ronald M.
AU - Abumrad, Nada A.
AU - Merghoub, Taha
AU - Wolchok, Jedd D.
AU - Shokhirev, Maxim N.
AU - Ho, Ping Chih
AU - Witztum, Joseph L.
AU - Emu, Brinda
AU - Cui, Guoliang
AU - Kaech, Susan M.
N1 - Funding Information: We thank Dr. Marcus W. Bosenberg for discussions; Dr. Annelise G. Snyder for graphics assistance; Dr. Anna-Maria Globig for assistance with RNA-seq; Dr. Hubert Tseng for grant applications; Drs. Thomas H. Mann and Heather M. McGee for manuscript review; Dr. Xuchu Que for technical assistance with preparation of oxidized LDL; Dr. Yao-cheng Li for assistance with cloning; C. O'Connor, Lara Boggeman, and C. Fitzpatrick at the Salk FACS core; Nasun Hah and Tzu-Wen Wang at the Salk Sequencing core; the UCSD FACS core for cell sorting; Dr. M. Valeria Estrada at the UCSD Histology core; and Faye McDonald for administrative assistance. We thank Dr. Yoav Altman from the Sanford Burnham Prebys Flow Cytometry Core, NCI grant P30 CA030199, and the James B. Pendleton Charitable Trust (which helped purchase the Amnis) for Amnis analysis. The NGS Core Facility of the Salk Institute is supported by funding from NIH-NCI CCSG P30 014195, the Chapman Foundation, and the Helmsley Charitable Trust. The Razavi Newman Integrative Genomics and Bioinformatics Core is supported by NIH/NGMS R01 GM102491-07, NIH/NCI P30 CA014195-46, NIA/NMG 1RF1AG064049-01, and the Helmsley Trust. The Mass Spectrometry Core of the Salk Institute is supported by funding from NIH-NCI CCSG P30 014195 and the Helmsley Center for Genomic Medicine. The MS data described here were gathered on a ThermoFisher Q Exactive Hybrid Quadrupole Orbitrap mass spectrometer funded by NIH grant 1S10OD021815-01. The Tissue Technology Shared Resource is supported by a NCI Cancer Center Support Grant (CCSG; P30CA23100). R.Z. is supported by the Parker Institute for Cancer Immunotherapy Bridge Scholar award. X.S. is supported by NIH grant K99HL148504. R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and supported by the NIH (DK057978, HL105278, and ES010337), the Cancer Center (CA014195), a NOMIS Foundation Distinguished Scientist and Scholar Award, the Lustgarten Foundation, and the Don and Lorraine Freeberg Foundation. G.C. is supported by a Helmholtz Young Investigator Award (Helmholtz Gemeinschaft, VH-NG-1113) and the German Research Foundation (Deutsche Forschungsgemeinschaft, CU375/7-1). This work was supported by the NIH (R01CA240909 to S.M.K, R01 CA206483 to S.M.K and B.E. R01 CA206483 supplemental to P.R.M, and R01HL148188 to X.S. and J.L.W.), the Melanoma Research Alliance (to S.M.K.), a Genentech Foundation fellowship (to S.X.), and a Salk innovation grant (to S.M.K. and R.M.E.). S.X. G.C. and S.M.K. conceptualized, designed, and supervised the research. S.X. performed experiments with assistance from P.R.-M. Z.X. D.C. V.T. Y.F. and S.K.V. O.C. performed human PBMC experiments. I.S. and R.Z. performed human TILs analysis. X.S. and W.T. helped with immunostaining of oxidized phospholipids. A.F.M.P. performed lipidomics analyses. A.W. J.S.L. S.K.V. and B.M. helped with gene expression analyses. M.D. R.M.E. N.A.A. T.M. J.D.W. M.N.S. P.-C.H. J.L.W. and B.E. provided scientific input. S.X. and S.M.K. prepared the manuscript. G.C. receives research funding from Bayer AG and Boehringer Ingelheim, but the funding is not relevant to the current study. J.L.W. and X.S. are named inventors on patent applications or patents related to the use of oxidation-specific antibodies held by UCSD. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4. R.Z. is a consultant for Leap Therapeutics and iTEOS. T.M. is a cofounder and holds equity in IMVAQ Therapeutics. T.M. is a consultant for Immunos Therapeutics, Pfizer, and Immunogenesis. T.M. has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. T.M. has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Georgiamune, Imvaq, Kyowa Hakko Kirin, Linneaus, Merck Pharmaceuticals, Neon Therapeutics, Polynoma, Psioxus, Recepta, Takara Bio, Trieza, Truvax, Sellas Life Sciences, Serametrix, Surface Oncology, Syndax, Syntalogic, and Werewolf Therapeutics. J.D.W. reports grants from Bristol Myers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals, Adaptive Biotechnologies, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. J.D.W. is an inventor on patent applications related to work on DNA vaccines in companion animals with cancer, assays for suppressive myeloid cells in blood, oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We thank Dr. Marcus W. Bosenberg for discussions; Dr. Annelise G. Snyder for graphics assistance; Dr. Anna-Maria Globig for assistance with RNA-seq; Dr. Hubert Tseng for grant applications; Drs. Thomas H. Mann and Heather M. McGee for manuscript review; Dr. Xuchu Que for technical assistance with preparation of oxidized LDL; Dr. Yao-cheng Li for assistance with cloning; C. O’Connor, Lara Boggeman, and C. Fitzpatrick at the Salk FACS core; Nasun Hah and Tzu-Wen Wang at the Salk Sequencing core; the UCSD FACS core for cell sorting; Dr. M. Valeria Estrada at the UCSD Histology core; and Faye McDonald for administrative assistance. We thank Dr. Yoav Altman from the Sanford Burnham Prebys Flow Cytometry Core, NCI grant P30 CA030199 , and the James B. Pendleton Charitable Trust (which helped purchase the Amnis) for Amnis analysis. The NGS Core Facility of the Salk Institute is supported by funding from NIH-NCI CCSG P30 014195 , the Chapman Foundation , and the Helmsley Charitable Trust . The Razavi Newman Integrative Genomics and Bioinformatics Core is supported by NIH/NGMS R01 GM102491-07 , NIH/NCI P30 CA014195-46 , NIA/NMG 1RF1AG064049-01 , and the Helmsley Trust . The Mass Spectrometry Core of the Salk Institute is supported by funding from NIH-NCI CCSG P30 014195 and the Helmsley Center for Genomic Medicine . The MS data described here were gathered on a ThermoFisher Q Exactive Hybrid Quadrupole Orbitrap mass spectrometer funded by NIH grant 1S10OD021815-01 . The Tissue Technology Shared Resource is supported by a NCI Cancer Center Support Grant (CCSG; P30CA23100 ). R.Z. is supported by the Parker Institute for Cancer Immunotherapy Bridge Scholar award. X.S. is supported by NIH grant K99HL148504 . R.M.E is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute and supported by the NIH ( DK057978 , HL105278 , and ES010337 ), the Cancer Center ( CA014195 ), a NOMIS Foundation Distinguished Scientist and Scholar Award, the Lustgarten Foundation , and the Don and Lorraine Freeberg Foundation . G.C. is supported by a Helmholtz Young Investigator Award ( Helmholtz Gemeinschaft , VH-NG-1113 ) and the German Research Foundation (Deutsche Forschungsgemeinschaft, CU375/7-1 ). This work was supported by the NIH ( R01CA240909 to S.M.K, R01 CA206483 to S.M.K and B.E., R01 CA206483 supplemental to P.R.M, and R01HL148188 to X.S. and J.L.W.), the Melanoma Research Alliance (to S.M.K.), a Genentech Foundation fellowship (to S.X.), and a Salk innovation grant (to S.M.K. and R.M.E.). Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021/7/13
Y1 - 2021/7/13
N2 - A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
AB - A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
KW - CD36
KW - CD8 T cells
KW - lipid peroxidation
KW - oxidized lipids
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85109445941&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2021.05.003
DO - 10.1016/j.immuni.2021.05.003
M3 - Article
C2 - 34102100
AN - SCOPUS:85109445941
SN - 1074-7613
VL - 54
SP - 1561-1577.e7
JO - Immunity
JF - Immunity
IS - 7
ER -