Using single-cell data of CD8+ TILs, Kim et al. show distinct expression patterns for CD28 in mouse and human tumors. In humans, CD28 expression by CD8+ T cells served as a marker for, but was functionally irrelevant to, anti-PD-1 antibody responsiveness. Human CD28-PD-1+CD8+ TILs show features of terminal exhaustion and high effector-like function, and were associated with poor prognosis and overall survival in anti-PD-1-treated patients with melanoma. IL-15 treatment ex vivo increased CD28-/CD28+ PD-1+CD8+ human TIL proliferation, and the combination of IL-15/IL-15Rα with anti-PD-1 enhanced antitumor response in a mouse tumor model.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Department of Radiation Oncology, Yonsei Can
Author Info: (1) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. (2) Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. (3) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (4) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (5) Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (6) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (7) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (8) Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (9) Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (10) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (11) Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea. (12) Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. (13) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. (14) Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea. silkahn@skku.edu. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. silkahn@skku.edu. (15) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. ecshin@kaist.ac.kr.
