Wang and Lu et al. highlight the role of intracellular PD-L1 in tumor-infiltrating CD8+ T cell dysfunction. In patients with ovarian cancer, intracellular PD-L1 was enriched in tumor-infiltrating CD8+ T cells, while surface PD-L1 was predominant in circulating CD8+ T cells. Cell-intrinsic, intracellular PD-L1 signaling inhibited the maintenance of effector-like CD8+ T cells and accelerated the transition toward a terminally exhausted state, partially via mTORC1-mediated metabolic reprogramming. Genetic ablation of PD-L1 in T cells resulted in enhanced antitumor immune response of therapeutic CD8+ T cells, and additionally boosted the CD103+ DC-dependent function of endogenous CD8+ T cells.
Contributed by Shishir Pant
ABSTRACT: Adoptive cell therapies are emerging forms of immunotherapy that reprogram T cells for enhanced antitumor responses. Although surface programmed cell death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) engagement inhibits antitumor immunity, the role of cell-intrinsic PD-L1 in adoptive T cell therapy remains unknown. Here, we found that intracellular PD-L1 was enriched in tumor-infiltrating CD8(+) T cells of cancer patients. PD-L1 ablation promoted antitumor immune responses and the maintenance of an effector-like state of therapeutic CD8(+) T cells, while blockade of surface PD-L1 was unable to impact on their expansion and function. Moreover, cell-intrinsic PD-L1 impeded CD8(+) T cell activity, which partially relied on mTORC1 signaling. Furthermore, endogenous tumor-reactive CD8(+) T cells were motivated by BATF3-driven dendritic cells after adoptive transfer of PD-L1-deficient therapeutic CD8(+) T cells. This role of cell-intrinsic PD-L1 in therapeutic CD8(+) T cell dysfunction highlights that disrupting cell-intrinsic PD-L1 in CD8(+) T cells represents a viable approach to improving T cell-based cancer immunotherapy.
Author Info: (1) Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicin
Author Info: (1) Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. (2) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China. (3) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (4) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China. (5) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China. (6) Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. (7) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (8) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (9) Shanghai Institute of Immunology, Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (10) Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: diwen@renji.com. (11) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Science, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: dengliufu@sjtu.edu.cn.
