Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-02, Vol.116 (7), p.2640-2645
• Main Authors: Nelson, Christine E., Mills, Lauren J., McCurtain, Jennifer L., Thompson, Emily A., Seelig, Davis M., Bhela, Siddheshvar, Quarnstrom, Clare F., Fife, Brian T., Vezys, Vaiva
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens - immunology; Antitumor activity; Autoimmunity; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Biological Sciences; CD223 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Proliferation; Cellular Reprogramming; Combinatorial analysis; CTLA-4 protein; Effector cells; Immune checkpoint; Immune Tolerance; Immunological tolerance; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; PD-1 protein; PD-L1 protein; Rapamycin; TOR protein; Transcription; Tumors; Vaccination
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1810326116

Established T cell dysfunction is a barrier to antitumor responses, and checkpoint blockade presumably reverses this. Many patients fail to respond to treatment and/or develop autoimmune adverse events. The underlying reason for T cell responsiveness remains elusive. Here, we show that susceptibility to checkpoint blockade is dependent on the activation status of T cells. Newly activated self-specific CD8 T cells respond to checkpoint blockade and cause autoimmunity, which is mitigated by inhibiting the mechanistic target of rapamycin. However, once tolerance is established, self-specific CD8 T cells display a gene signature comparable to tumor-specific CD8 T cells in a fixed state of dysfunction. Tolerant self-specific CD8 T cells do not respond to single or combinatorial dosing of anti-CTLA4, anti–PD-L1, anti–PD-1, anti–LAG-3, and/or anti–TIM-3. Despite this, T cell responsiveness can be induced by vaccination with cognate antigen, which alters the previously fixed transcriptional signature and increases antigen-sensing machinery. Antigenic reeducation of tolerant T cells synergizes with checkpoint blockade to generate functional CD8 T cells, which eliminate tumors without concomitant autoimmunity and are transcriptionally distinct from classic effector T cells. These data demonstrate that responses to checkpoint blockade are dependent on the activation state of a T cell and show that checkpoint blockade-insensitive CD8 T cells can be induced to respond to checkpoint blockade with robust antigenic stimulation to participate in tumor control.