Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved December 20, 2018 (received for review June 14, 2018)
Cancer immunotherapies, such as immune checkpoint blockade, work by stimulating immune cells to kill tumors. Unfortunately, not all patients respond to checkpoint treatment, which also causes autoimmune side effects due to self-reactive immune cell activation. This study uncovers immune subtypes that respond best to this immunotherapy and reveals methods to reinvigorate dysfunctional antitumor immune responses. We show that self-reactive CD8 T cells can be pathogenic or nonresponsive to checkpoint blockade therapy depending on their activation status. In addition, tolerant self-reactive CD8 T cells bear striking similarity to dysfunctional tumor-specific CD8 T cells. Finally, we demonstrate that previously tolerant self-specific CD8 T cells can eliminate aggressive tumors bearing self-antigens without concomitant autoimmunity after robust antigenic vaccination in concert with PD-L1 blockade.
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 contributions: C.E.N. and V.V. designed research; C.E.N., J.L.M., E.A.T., S.B., and C.F.Q. performed research; B.T.F. contributed new reagents/analytic tools; C.E.N., L.J.M., J.L.M., E.A.T., D.M.S., S.B., C.F.Q., and V.V. analyzed data; and C.E.N., E.A.T., C.F.Q., B.T.F., and V.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1810326116/-/DCSupplemental.
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