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PD-1 blockade-unresponsive human tumor-infiltrating CD8 + T cells are marked by loss of CD28 expression and rescued by IL-15

 Kyung Hwan Kim  ;  Hong Kwan Kim  ;  Hyung-Don Kim  ;  Chang Gon Kim  ;  Hoyoung Lee  ;  Ji Won Han  ;  Seong Jin Choi  ;  Seongju Jeong  ;  Minwoo Jeon  ;  Hyunglae Kim  ;  Jiae Koh  ;  Bo Mi Ku  ;  Su-Hyung Park  ;  Myung-Ju Ahn  ;  Eui-Cheol Shin 
 CELLULAR & MOLECULAR IMMUNOLOGY, Vol.18(2) : 385-397, 2021-02 
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CD28 ; IL-15 ; T cells ; TCF1 ; anti-PD-1
Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+ but not CD28-CD8+ TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28-PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28-PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28-PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8+ TILs with a TCF1- signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Kim, Chang Gon(김창곤)
Shin, Ui Cheol(신의철)
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