Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 50; no. 1; pp. 181 - 194.e6
• Main Authors: Kurtulus, Sema, Madi, Asaf, Escobar, Giulia, Klapholz, Max, Nyman, Jackson, Christian, Elena, Pawlak, Mathias, Dionne, Danielle, Xia, Junrong, Rozenblatt-Rosen, Orit, Kuchroo, Vijay K., Regev, Aviv, Anderson, Ana C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2019; Elsevier Limited
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antigens, Neoplasm - immunology; Cancer; CD8 antigen; CD8+ T cell; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; checkpoint blockade; dysfunction; Effector cells; exhaustion; Gene expression; Hepatitis A Virus Cellular Receptor 2 - antagonists & inhibitors; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Immune checkpoint; Immunoglobulins; Immunologic Memory - genetics; Immunological memory; Immunotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma, Experimental; memory; Memory cells; Mice; Mice, Inbred C57BL; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; PD-1; PD-1 protein; Population; Precursors; Principal components analysis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Ribonucleic acid; RNA; single-cell; Software; T-Lymphocyte Subsets - immunology; Tim-3; Transcription; Transcription factors; Transcriptome; Tumor-infiltrating lymphocytes; Tumors; checkpoint blockade; memory; immunotherapy; single-cell; exhaustion; CD8+ T cell; cancer; PD-1; dysfunction; Tim-3; CD8(+) T cell
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.11.014

An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1− TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy. [Display omitted] •Checkpoint blockade induces transcriptional changes in PD-1−CD8+ and PD-1+CD8+ TILs•PD-1−CD8+ TILs contain naive-, memory-precursor-, and effector-like subsets•Memory-precursor- and effector-like PD-1−CD8+ TILs expand upon checkpoint blockade•Tcf7 is required for memory-precursor-like cells and efficacy of immunotherapies Kurtulus et al. examine the dynamics of the effector CD8+ T cell response in the tumor microenvironment in response to checkpoint blockade immunotherapy. Checkpoint blockade induced a shift from naive-like to memory-precursor- and effector-like subsets within PD-1−CD8+ T cells in tumors. The memory-precursor-like subset is maintained by the transcriptional regulator Tcf7/Tcf1, which is required for efficacy of checkpoint blockade and other immunotherapies.