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

Nat Immunol. 2019 Sep;20(9):1231-1243. doi: 10.1038/s41590-019-0441-y. Epub 2019 Jul 29.

Authors

Vivek Verma^{1

2}, Rajeev K Shrimali^{1

3}, Shamim Ahmad^{1

4}, Winjie Dai¹, Hua Wang¹, Sumin Lu¹, Rahul Nandre^{1

2}, Pankaj Gaur^{1

2}, Jose Lopez², Moshe Sade-Feldman^{5

6}, Keren Yizhak⁶, Stacey L Bjorgaard^{5

6}, Keith T Flaherty⁵, Jennifer A Wargo⁷, Genevieve M Boland⁸, Ryan J Sullivan⁵, Gad Getz^{5

6

9}, Scott A Hammond¹⁰, Ming Tan¹¹, Jingjing Qi¹², Phillip Wong¹², Taha Merghoub^{12

13}, Jedd Wolchok^{12

13}, Nir Hacohen^{5

6}, John E Janik^{1

14}, Mikayel Mkrtichyan^{1

2

15}, Seema Gupta^{1

2}, Samir N Khleif^{16

17}

Affiliations

¹ Georgia Cancer Center, Augusta University, Augusta, GA, USA.
² The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
³ Therapeutic Discovery, MD Anderson Cancer Center, Houston, TX, USA.
⁴ Five Prime Therapeutics Inc., South San Francisco, CA, USA.
⁵ Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
⁶ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁷ Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ MedImmune LLC, Gaithersburg, MD, USA.
¹¹ Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University, Washington, DC, USA.
¹² Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹³ Weill Cornell Medical and Graduate Schools, New York, NY, USA.
¹⁴ Incyte Inc., Wilmington, DE, USA.
¹⁵ A2 Biotherapeutics, Agoura Hills, CA, USA.
¹⁶ Georgia Cancer Center, Augusta University, Augusta, GA, USA. snk48@georgetown.edu.
¹⁷ The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. snk48@georgetown.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ADP-ribosyl Cyclase 1 / genetics
ADP-ribosyl Cyclase 1 / metabolism*
Animals
Antibodies / immunology
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology
Cancer Vaccines / immunology
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Drug Resistance, Neoplasm / immunology*
Female
Humans
Immunotherapy / methods
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasms / immunology*
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / immunology*
Tumor Microenvironment / immunology

Substances

Antibodies
Cancer Vaccines
Membrane Glycoproteins
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Cd38 protein, mouse
ADP-ribosyl Cyclase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding