The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

Andrew Chow; Fathema Z. Uddin; Michael Liu; Anton Dobrin; Barzin Y. Nabet; Levi Mangarin; Yonit Lavin; Hira Rizvi; Sam E. Tischfield; Alvaro Quintanal-Villalonga; Joseph M. Chan; Nisargbhai Shah; Viola Allaj; Parvathy Manoj; Marissa Mattar; Maximiliano Meneses; Rebecca Landau; Mariana Ward; Amanda Kulick; Charlene Kwong; Matthew Wierzbicki; Jessica Yavner; Jacklynn Egger; Shweta S. Chavan; Abigail Farillas; Aliya Holland; Harsha Sridhar; Metamia Ciampricotti; Daniel Hirschhorn; Xiangnan Guan; Allison L. Richards; Glenn Heller; Jorge Mansilla-Soto; Michel Sadelain; Christopher A. Klebanoff; Matthew D. Hellmann; Triparna Sen; Elisa de Stanchina; Jedd D. Wolchok; Taha Merghoub; Charles M. Rudin

doi:10.1016/j.immuni.2022.12.001

The ectonucleotidase CD39 identifies tumor-reactive CD8⁺ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

Andrew Chow, Fathema Z. Uddin, Michael Liu, Anton Dobrin, Barzin Y. Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E. Tischfield, Alvaro Quintanal-Villalonga, Joseph M. Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene KwongMatthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S. Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L. Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A. Klebanoff, Matthew D. Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D. Wolchok, Taha Merghoub, Charles M. Rudin

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8⁺ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8⁺ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39⁺ CD8⁺ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39⁺ CD8⁺ T cells. Higher baseline frequency of CD39⁺ CD8⁺ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39⁺ CD8⁺ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8⁺ T cells in human lung cancer.

Original language	English
Pages (from-to)	93-106.e6
Journal	Immunity
Volume	56
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2022.12.001
State	Published - 10 Jan 2023
Externally published	Yes

Keywords

CD8 T cells
T cell receptors
immune checkpoint blockade
non-small cell lung cancer
tumor mutation burden

Access to Document

10.1016/j.immuni.2022.12.001

Cite this

Chow, A., Uddin, F. Z., Liu, M., Dobrin, A., Nabet, B. Y., Mangarin, L., Lavin, Y., Rizvi, H., Tischfield, S. E., Quintanal-Villalonga, A., Chan, J. M., Shah, N., Allaj, V., Manoj, P., Mattar, M., Meneses, M., Landau, R., Ward, M., Kulick, A., ... Rudin, C. M. (2023). The ectonucleotidase CD39 identifies tumor-reactive CD8⁺ T cells predictive of immune checkpoint blockade efficacy in human lung cancer. Immunity, 56(1), 93-106.e6. https://doi.org/10.1016/j.immuni.2022.12.001

@article{3d1737c300894731b3199964d72bd41e,

title = "The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer",

abstract = "Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.",

keywords = "CD8 T cells, T cell receptors, immune checkpoint blockade, non-small cell lung cancer, tumor mutation burden",

author = "Andrew Chow and Uddin, {Fathema Z.} and Michael Liu and Anton Dobrin and Nabet, {Barzin Y.} and Levi Mangarin and Yonit Lavin and Hira Rizvi and Tischfield, {Sam E.} and Alvaro Quintanal-Villalonga and Chan, {Joseph M.} and Nisargbhai Shah and Viola Allaj and Parvathy Manoj and Marissa Mattar and Maximiliano Meneses and Rebecca Landau and Mariana Ward and Amanda Kulick and Charlene Kwong and Matthew Wierzbicki and Jessica Yavner and Jacklynn Egger and Chavan, {Shweta S.} and Abigail Farillas and Aliya Holland and Harsha Sridhar and Metamia Ciampricotti and Daniel Hirschhorn and Xiangnan Guan and Richards, {Allison L.} and Glenn Heller and Jorge Mansilla-Soto and Michel Sadelain and Klebanoff, {Christopher A.} and Hellmann, {Matthew D.} and Triparna Sen and {de Stanchina}, Elisa and Wolchok, {Jedd D.} and Taha Merghoub and Rudin, {Charles M.}",

note = "Funding Information: We are grateful for experimental support from the MSKCC Molecular Cytology Core Facility , Flow Cytometry Core Facility , and Integrated Genomics Operation Core (funded by the NCI Cancer Center Support Grant [CCSG, P30 CA08748 ], Cycle for Survival , and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology ). We are grateful for manuscript editing provided by Dr. Clare Wilhelm and Reeja Thomas. This research was funded in part through the NIH NCI CCSG P30 CA008748 , NCI R01 CA056821 , U24 CA213274 , P01 CA129243 , R01 CA197936 , R37 CA259177 (to C.A.K.), Cancer Research Institute CRI3176 (to C.A.K.), Stony Wold Herbert Fund , International Association of Lung Cancer Research (IASLC)/ International Lung Cancer Foundation (ILCF), the MSKCC Society Grant , the Ludwig Collaborative and Swim Across America Laboratory , the Emerald Foundation , the Parker Institute for Cancer Immunotherapy at MSKCC , the Department of Medicine at MSKCC , Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant ( SU2C-AACR-DT17-15 ), Mark Foundation for Cancer Research (grant # 19-029-MIA ), Kay Stafford Fund, and Gibbons Scattone Family Foundation . 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 ). Funding Information: C.A.K. received research funding support from Kite/Gilead and Intima Bioscience; is on the Scientific and/or Clinical Advisory Boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics, and T-knife; and has performed consulting services for Bristol Myers Squibb, PACT Pharma, and Roche/Genentech. C.A.K. is a co-inventor on patent applications related to TCRs targeting public neoantigens unrelated to the current work. M.D.H. received a 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, and Syndax; and 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. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, and Werewolf Therapeutics. J.D.W. receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. 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. B.Y.N. and X.G. are employees and stockholders of Genentech/Roche. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2023",

month = jan,

day = "10",

doi = "10.1016/j.immuni.2022.12.001",

language = "English",

volume = "56",

pages = "93--106.e6",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "1",

}

Chow, A, Uddin, FZ, Liu, M, Dobrin, A, Nabet, BY, Mangarin, L, Lavin, Y, Rizvi, H, Tischfield, SE, Quintanal-Villalonga, A, Chan, JM, Shah, N, Allaj, V, Manoj, P, Mattar, M, Meneses, M, Landau, R, Ward, M, Kulick, A, Kwong, C, Wierzbicki, M, Yavner, J, Egger, J, Chavan, SS, Farillas, A, Holland, A, Sridhar, H, Ciampricotti, M, Hirschhorn, D, Guan, X, Richards, AL, Heller, G, Mansilla-Soto, J, Sadelain, M, Klebanoff, CA, Hellmann, MD, Sen, T, de Stanchina, E, Wolchok, JD, Merghoub, T & Rudin, CM 2023, 'The ectonucleotidase CD39 identifies tumor-reactive CD8⁺ T cells predictive of immune checkpoint blockade efficacy in human lung cancer', Immunity, vol. 56, no. 1, pp. 93-106.e6. https://doi.org/10.1016/j.immuni.2022.12.001

TY - JOUR

T1 - The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer

AU - Chow, Andrew

AU - Uddin, Fathema Z.

AU - Liu, Michael

AU - Dobrin, Anton

AU - Nabet, Barzin Y.

AU - Mangarin, Levi

AU - Lavin, Yonit

AU - Rizvi, Hira

AU - Tischfield, Sam E.

AU - Quintanal-Villalonga, Alvaro

AU - Chan, Joseph M.

AU - Shah, Nisargbhai

AU - Allaj, Viola

AU - Manoj, Parvathy

AU - Mattar, Marissa

AU - Meneses, Maximiliano

AU - Landau, Rebecca

AU - Ward, Mariana

AU - Kulick, Amanda

AU - Kwong, Charlene

AU - Wierzbicki, Matthew

AU - Yavner, Jessica

AU - Egger, Jacklynn

AU - Chavan, Shweta S.

AU - Farillas, Abigail

AU - Holland, Aliya

AU - Sridhar, Harsha

AU - Ciampricotti, Metamia

AU - Hirschhorn, Daniel

AU - Guan, Xiangnan

AU - Richards, Allison L.

AU - Heller, Glenn

AU - Mansilla-Soto, Jorge

AU - Sadelain, Michel

AU - Klebanoff, Christopher A.

AU - Hellmann, Matthew D.

AU - Sen, Triparna

AU - de Stanchina, Elisa

AU - Wolchok, Jedd D.

AU - Merghoub, Taha

AU - Rudin, Charles M.

N1 - Funding Information: We are grateful for experimental support from the MSKCC Molecular Cytology Core Facility , Flow Cytometry Core Facility , and Integrated Genomics Operation Core (funded by the NCI Cancer Center Support Grant [CCSG, P30 CA08748 ], Cycle for Survival , and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology ). We are grateful for manuscript editing provided by Dr. Clare Wilhelm and Reeja Thomas. This research was funded in part through the NIH NCI CCSG P30 CA008748 , NCI R01 CA056821 , U24 CA213274 , P01 CA129243 , R01 CA197936 , R37 CA259177 (to C.A.K.), Cancer Research Institute CRI3176 (to C.A.K.), Stony Wold Herbert Fund , International Association of Lung Cancer Research (IASLC)/ International Lung Cancer Foundation (ILCF), the MSKCC Society Grant , the Ludwig Collaborative and Swim Across America Laboratory , the Emerald Foundation , the Parker Institute for Cancer Immunotherapy at MSKCC , the Department of Medicine at MSKCC , Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Dream Team Translational research grant ( SU2C-AACR-DT17-15 ), Mark Foundation for Cancer Research (grant # 19-029-MIA ), Kay Stafford Fund, and Gibbons Scattone Family Foundation . 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 ). Funding Information: C.A.K. received research funding support from Kite/Gilead and Intima Bioscience; is on the Scientific and/or Clinical Advisory Boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics, and T-knife; and has performed consulting services for Bristol Myers Squibb, PACT Pharma, and Roche/Genentech. C.A.K. is a co-inventor on patent applications related to TCRs targeting public neoantigens unrelated to the current work. M.D.H. received a 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, and Syndax; and 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. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, and Werewolf Therapeutics. J.D.W. receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals, and Trieza. J.D.W. is a co-inventor on the following patent application: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. J.D.W. and T.M. are co-inventors on patent applications related to CD40 and in situ vaccination (PCT/US2016/045970). T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. receives research funding from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. T.M. 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. B.Y.N. and X.G. are employees and stockholders of Genentech/Roche. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2023/1/10

Y1 - 2023/1/10

N2 - Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.

AB - Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.

KW - CD8 T cells

KW - T cell receptors

KW - immune checkpoint blockade

KW - non-small cell lung cancer

KW - tumor mutation burden

UR - http://www.scopus.com/inward/record.url?scp=85145981685&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2022.12.001

DO - 10.1016/j.immuni.2022.12.001

M3 - Article

C2 - 36574773

AN - SCOPUS:85145981685

SN - 1074-7613

VL - 56

SP - 93-106.e6

JO - Immunity

JF - Immunity

IS - 1