Nelson et al. demonstrated that newly transferred self-antigen specific CD8+ T cells are activated and respond to immune checkpoint blockade (ICB), but lead to intestinal toxicities. Tolerized self-specific T cells (30 days after transfer) appear to be in a fixed state of dysfunction and do not respond to monotherapies or combinations of ICBs; however, stimulation with an infection-inducing live viral vector expressing the cognate self-antigen increased proliferation and inhibitory receptor expression. The viral vector synergized with anti-PD-L1 to control self-antigen-expressing melanoma without inducing toxicities.
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.
Author Info: (1) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. Center for Immunology, University of Minnesota, Minneapolis, MN 55455. (2) Minnesota
Author Info: (1) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. Center for Immunology, University of Minnesota, Minneapolis, MN 55455. (2) Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN (3) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. (4) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. Center for Immunology, University of Minnesota, Minneapolis, MN 55455. (5) Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN (6) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. Center for Immunology, University of Minnesota, Minneapolis, MN 55455. (7) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455. Center for Immunology, University of Minnesota, Minneapolis, MN 55455. (8) Center for Immunology, University of Minnesota, Minneapolis, MN 55455. Department of Medicine, University of Minnesota, Minneapolis, MN 55455. (9) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455; vvezys@umn.edu. Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
