PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance

Vivek Verma; Rajeev K. Shrimali; Shamim Ahmad; Winjie Dai; Hua Wang; Sumin Lu; Rahul Nandre; Pankaj Gaur; Jose Lopez; Moshe Sade-Feldman; Keren Yizhak; Stacey L. Bjorgaard; Keith T. Flaherty; Jennifer A. Wargo; Genevieve M. Boland; Ryan J. Sullivan; Gad Getz; Scott A. Hammond; Ming Tan; Jingjing Qi; Phillip Wong; Taha Merghoub; Jedd Wolchok; Nir Hacohen; John E. Janik; Mikayel Mkrtichyan; Seema Gupta; Samir N. Khleif

doi:10.1038/s41590-019-0441-y

PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1⁺CD38^hi cells and anti-PD-1 resistance

Vivek Verma, Rajeev K. Shrimali, Shamim Ahmad, Winjie Dai, Hua Wang, Sumin Lu, Rahul Nandre, Pankaj Gaur, Jose Lopez, Moshe Sade-Feldman, Keren Yizhak, Stacey L. Bjorgaard, Keith T. Flaherty, Jennifer A. Wargo, Genevieve M. Boland, Ryan J. Sullivan, Gad Getz, Scott A. Hammond, Ming Tan, Jingjing QiPhillip Wong, Taha Merghoub, Jedd Wolchok, Nir Hacohen, John E. Janik, Mikayel Mkrtichyan, Seema Gupta, Samir N. Khleif

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

Abstract

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1⁺CD38^hi CD8⁺ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1⁺CD38^hi CD8⁺ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1⁺CD38⁺CD8⁺ cells in tumor and blood than responders. In conclusion, the status of CD8⁺ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1⁺CD38^hi CD8⁺ cells that is reversed by optimal priming. PD-1⁺CD38^hi CD8⁺ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

Original language	English
Pages (from-to)	1231-1243
Number of pages	13
Journal	Nature Immunology
Volume	20
Issue number	9
DOIs	https://doi.org/10.1038/s41590-019-0441-y
State	Published - 1 Sep 2019
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41590-019-0441-y

Cite this

Verma, V., Shrimali, R. K., Ahmad, S., Dai, W., Wang, H., Lu, S., Nandre, R., Gaur, P., Lopez, J., Sade-Feldman, M., Yizhak, K., Bjorgaard, S. L., Flaherty, K. T., Wargo, J. A., Boland, G. M., Sullivan, R. J., Getz, G., Hammond, S. A., Tan, M., ... Khleif, S. N. (2019). PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1⁺CD38^hi cells and anti-PD-1 resistance. Nature Immunology, 20(9), 1231-1243. https://doi.org/10.1038/s41590-019-0441-y

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title = "PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance",

abstract = "Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.",

author = "Vivek Verma and Shrimali, {Rajeev K.} and Shamim Ahmad and Winjie Dai and Hua Wang and Sumin Lu and Rahul Nandre and Pankaj Gaur and Jose Lopez and Moshe Sade-Feldman and Keren Yizhak and Bjorgaard, {Stacey L.} and Flaherty, {Keith T.} and Wargo, {Jennifer A.} and Boland, {Genevieve M.} and Sullivan, {Ryan J.} and Gad Getz and Hammond, {Scott A.} and Ming Tan and Jingjing Qi and Phillip Wong and Taha Merghoub and Jedd Wolchok and Nir Hacohen and Janik, {John E.} and Mikayel Mkrtichyan and Seema Gupta and Khleif, {Samir N.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = sep,

day = "1",

doi = "10.1038/s41590-019-0441-y",

language = "אנגלית",

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Verma, V, Shrimali, RK, Ahmad, S, Dai, W, Wang, H, Lu, S, Nandre, R, Gaur, P, Lopez, J, Sade-Feldman, M, Yizhak, K, Bjorgaard, SL, Flaherty, KT, Wargo, JA, Boland, GM, Sullivan, RJ, Getz, G, Hammond, SA, Tan, M, Qi, J, Wong, P, Merghoub, T, Wolchok, J, Hacohen, N, Janik, JE, Mkrtichyan, M, Gupta, S & Khleif, SN 2019, 'PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1⁺CD38^hi cells and anti-PD-1 resistance', Nature Immunology, vol. 20, no. 9, pp. 1231-1243. https://doi.org/10.1038/s41590-019-0441-y

TY - JOUR

T1 - PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance

AU - Verma, Vivek

AU - Shrimali, Rajeev K.

AU - Ahmad, Shamim

AU - Dai, Winjie

AU - Wang, Hua

AU - Lu, Sumin

AU - Nandre, Rahul

AU - Gaur, Pankaj

AU - Lopez, Jose

AU - Sade-Feldman, Moshe

AU - Yizhak, Keren

AU - Bjorgaard, Stacey L.

AU - Flaherty, Keith T.

AU - Wargo, Jennifer A.

AU - Boland, Genevieve M.

AU - Sullivan, Ryan J.

AU - Getz, Gad

AU - Hammond, Scott A.

AU - Tan, Ming

AU - Qi, Jingjing

AU - Wong, Phillip

AU - Merghoub, Taha

AU - Wolchok, Jedd

AU - Hacohen, Nir

AU - Janik, John E.

AU - Mkrtichyan, Mikayel

AU - Gupta, Seema

AU - Khleif, Samir N.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

AB - Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.

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