Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Cell |
| Vol/bind | 39 |
| Udgave nummer | 12 |
| Sider (fra-til) | 1623-1642.e20 |
| ISSN | 1535-6108 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
The study was supported by NIH grants P50 CA083638 SPORE in Ovarian Cancer, R01-CA116779, R01-CA098951; U54-CA225088; the Ludwig Institute for Cancer Research; grants from the Ovarian Cancer Research Alliance, Sidney Kimmel Foundation, Cancera Foundation, Mats Paulsson Foundation (all to G.C.); by NIH grant U54-CA225088 (to P.K.S.); and by RO1EB026892 grant (to D.J.P.). We thank Danny Labes from FCF@UNIL for performing the cell sorting for the scRNA-seq, and Michel A. Cuendet and Ekaterina Fortis for assisting with the melanoma cohort staining. Conceptualization, G.C.; supervision, G.C. M.A.D. and D.D.L.; methodology, G.C. J.D. M.A.D. R.T. D.D.L. A. Minasyan, S.R. P.G.F. P.K.S. and W.C.; validation, G.C. D.D.L. and M.A.D.; writing, G.C. P.K.S. D.D.L. A Minasyan, R.T. M.A.D. D.B. I.C. J.C. A.F. and R.G.; analysis, G.C. J.D. R.T. A. Minasyan, J.C. A.F. S.J.C. K.I. A.J.G. D.B. I.C. F.B. A.W. R.G. M.A.E. W.C. V.Z. P.G.F. M.D. S.R. D.J.P.J. I.M.S. and C.A.J.; investigation, J.D. R.T. A. Minasyan, K.I. A.W. W.C. C.N. P.G.F. A.J.G. A. Moriot, S.R.-T. N.F. V.A. M.A.E. M.C.W.W. and I.M.S.; resources, J.L.T. D.D.L. K.T.M. M.A.E. L.E.K. and O.M. G.C. has received grants from Celgene, Boehringer-Ingelheim, BMS, and Tigen, and participated in advisory board or presented at Roche, MSD Merck, BMS, AstraZeneca, and Geneos Tx-sponsored symposia (fees received by G.C.?s institution). G.C. has patents in the domain of antibodies, vaccines, T cell expansion, and engineering technologies, and receives royalties from UPenn. P.K.S. is a member of the SAB or Board of Directors of Applied Biomath, Glencoe Software, RareCyte Inc. and has equities in these companies; he is a member of the SAB of NanoString Inc. and a consultant for Merck and Montai Health. P.K.S. has received research funding from Novartis and Merck. D.J.P. receives research funding from Incyte and serves as an adviser, receives fees, stock options, and research funding from InsTIL Bio. R.G. holds a patent for TCR sequencing. J.D. is presently a US FDA employee. R.T. C.N. V.A. and M.A.D. are current employees of Ichnos Sciences Biotherapeutics SA. None of the above declared relationships has influenced the content of this manuscript. The other authors declare no competing financial interests.
Funding Information:
The study was supported by NIH grants P50 CA083638 SPORE in Ovarian Cancer, R01-CA116779 , R01-CA098951 ; U54-CA225088 ; the Ludwig Institute for Cancer Research ; grants from the Ovarian Cancer Research Alliance, Sidney Kimmel Foundation , Cancera Foundation, Mats Paulsson Foundation (all to G.C.); by NIH grant U54-CA225088 (to P.K.S.); and by RO1EB026892 grant (to D.J.P.). We thank Danny Labes from FCF@UNIL for performing the cell sorting for the scRNA-seq, and Michel A. Cuendet and Ekaterina Fortis for assisting with the melanoma cohort staining.
Funding Information:
G.C. has received grants from Celgene , Boehringer-Ingelheim , BMS , and Tigen , and participated in advisory board or presented at Roche , MSD Merck , BMS , AstraZeneca , and Geneos Tx -sponsored symposia (fees received by G.C.’s institution). G.C. has patents in the domain of antibodies, vaccines, T cell expansion, and engineering technologies, and receives royalties from UPenn. P.K.S. is a member of the SAB or Board of Directors of Applied Biomath, Glencoe Software, RareCyte Inc., and has equities in these companies; he is a member of the SAB of NanoString Inc. and a consultant for Merck and Montai Health. P.K.S. has received research funding from Novartis and Merck . D.J.P. receives research funding from Incyte and serves as an adviser, receives fees, stock options, and research funding from InsTIL Bio . R.G. holds a patent for TCR sequencing. J.D. is presently a US FDA employee. R.T., C.N., V.A., and M.A.D. are current employees of Ichnos Sciences Biotherapeutics SA. None of the above declared relationships has influenced the content of this manuscript. The other authors declare no competing financial interests.
Publisher Copyright:
© 2021 Elsevier Inc.
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