TY - JOUR
T1 - NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer
AU - Salomé, Bérengère
AU - Sfakianos, John P.
AU - Ranti, Daniel
AU - Daza, Jorge
AU - Bieber, Christine
AU - Charap, Andrew
AU - Hammer, Christian
AU - Banchereau, Romain
AU - Farkas, Adam M.
AU - Ruan, Dan Fu
AU - Izadmehr, Sudeh
AU - Geanon, Daniel
AU - Kelly, Geoffrey
AU - de Real, Ronaldo M.
AU - Lee, Brian
AU - Beaumont, Kristin G.
AU - Shroff, Sanjana
AU - Wang, Yuanshuo A.
AU - Wang, Ying chih
AU - Thin, Tin Htwe
AU - Garcia-Barros, Monica
AU - Hegewisch-Solloa, Everardo
AU - Mace, Emily M.
AU - Wang, Li
AU - O'Donnell, Timothy
AU - Chowell, Diego
AU - Fernandez-Rodriguez, Ruben
AU - Skobe, Mihaela
AU - Taylor, Nicole
AU - Kim-Schulze, Seunghee
AU - Sebra, Robert P.
AU - Palmer, Doug
AU - Clancy-Thompson, Eleanor
AU - Hammond, Scott
AU - Kamphorst, Alice O.
AU - Malmberg, Karl Johan
AU - Marcenaro, Emanuela
AU - Romero, Pedro
AU - Brody, Rachel
AU - Viard, Mathias
AU - Yuki, Yuko
AU - Martin, Maureen
AU - Carrington, Mary
AU - Mehrazin, Reza
AU - Wiklund, Peter
AU - Mellman, Ira
AU - Mariathasan, Sanjeev
AU - Zhu, Jun
AU - Galsky, Matthew D.
AU - Bhardwaj, Nina
AU - Horowitz, Amir
N1 - Funding Information:
We thank Miriam Merad (Precision Immunology Institute, Icahn School of Medicine at Mount Sinai) for critically reviewing the manuscript; Deepta Bhattacharyá (University of Arizona) for kindly providing HLA-E + K562 tumors; and Mary Anne O’Donnell for critical review of manuscript. We acknowledge the expertise and assistance of the Dean’s Flow Cytometry Center of Research Excellence at Mount Sinai. HLA genotyping was funded in whole or in part in M.C.’s lab with federal funds from the Frederick National Laboratory for Cancer Research , under contract no. HHSN261200800001E , and was supported in part by the Intramural Research Program of the NIH , Frederick National Lab , Center for Cancer Research . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NKG2D, NKp30, and NKp46 blocking antibodies were provided by the E.M. lab, and the work was supported by Compagnia di San Paolo ( 2019.866 ) and Fondazione Associazione Italiana per la Ricerca sul Cancro ( AIRC IG2021–ID26037 ). The N.B. lab was supported by funding from the Department of Defense Peer Review Cancer Research program Translational team award no. W81XWH1910269 and from the Parker Institute for Cancer Immunotherapy No. AGR-11611SOW1 . The A.H. lab was supported by funding from P30CA196521 and RAI130760A . S.I. is supported by the Loan Repayment Program , NCATS , NIH and T32 Training Program in Cancer Biology T32CA078207 , NCI , NIH .
Funding Information:
We thank Miriam Merad (Precision Immunology Institute, Icahn School of Medicine at Mount Sinai) for critically reviewing the manuscript; Deepta Bhattacharyá (University of Arizona) for kindly providing HLA-E+ K562 tumors; and Mary Anne O'Donnell for critical review of manuscript. We acknowledge the expertise and assistance of the Dean's Flow Cytometry Center of Research Excellence at Mount Sinai. HLA genotyping was funded in whole or in part in M.C.’s lab with federal funds from the Frederick National Laboratory for Cancer Research, under contract no. HHSN261200800001E, and was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NKG2D, NKp30, and NKp46 blocking antibodies were provided by the E.M. lab, and the work was supported by Compagnia di San Paolo (2019.866) and Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC IG2021–ID26037). The N.B. lab was supported by funding from the Department of Defense Peer Review Cancer Research program Translational team award no. W81XWH1910269 and from the Parker Institute for Cancer Immunotherapy No.AGR-11611SOW1. The A.H. lab was supported by funding from P30CA196521 and RAI130760A. S.I. is supported by the Loan Repayment Program, NCATS, NIH and T32 Training Program in Cancer Biology T32CA078207, NCI, NIH. B.S. N.B. and A.H. conceived the project and experiments, analyzed data, and wrote the manuscript. J.P.S. R.M. P.W. M.G. N.T. and R.B. provided access to the human samples. E.M. provided reagents. B.S. J.D. D.R. C.B. and A.C. performed the experiments. J.Z. M.V. T.O.D. and D.C. performed the LOH HLA and FACETS analyses. A.M.F. J.Z. K.G.B. L.W. R.P.S. S.S. Y.-C.W. and Y.A.W. collected RNA sequencing data. D.G. G.K. R.M.d.-R. B.L. and S.K.-S. acquired sample data using the mass cytometer. T.H.T. M.G.-B. R.B. E.H.-S. E.M.M. C.B. R.F.-G. and M.S. performed the imaging experiments. M.C. Y.Y. and M.M. performed HLA genotyping analyses. C.H. R.B. and S.M. performed ImVigor 210 analyses. A.O.K. E.M. I.M. K.-J.M. and P.R. provided intellectual input. L.W. R.P.S. and J.Z. are employees of Sema4. A.H. receives research funds from Zumutor Biologics and is on the advisory boards of HTG Molecular Diagnostics, Immunorizon, UroGen, and Takeda. N.B. is an extramural member of the Parker Institute for Cancer Immunotherapy; receives research funds from Regeneron, Harbor Biomedical, DC Prime, and Dragonfly Therapeutics; and is on the advisory boards of Neon Therapeutics, Novartis, Avidea, Boehringer Ingelheim, Rome Therapeutics, Rubius Therapeutics, Roswell Park Comprehensive Cancer Center, BreakBio, Carisma Therapeutics, CureVac, Genotwin, BioNTech, Gilead Therapeutics, Tempest Therapeutics, and the Cancer Research Institute. A patent related to this work was filed to the United States Patent and Trademark Office (63/313,823).
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9/12
Y1 - 2022/9/12
N2 - Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.
AB - Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E.
KW - CD8 T cells
KW - HLA class I
KW - NK cells
KW - NKG2A
KW - bladder cancer
KW - checkpoint blockade immunotherapy
KW - immune exhaustion
KW - solid tumors
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85137401890&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2022.08.005
DO - 10.1016/j.ccell.2022.08.005
M3 - Article
AN - SCOPUS:85137401890
SN - 1535-6108
VL - 40
SP - 1027-1043.e9
JO - Cancer Cell
JF - Cancer Cell
IS - 9
ER -