TY - JOUR
T1 - Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells
AU - Nelson, Christine E.
AU - Mills, Lauren J.
AU - McCurtain, Jennifer L.
AU - Thompson, Emily A.
AU - Seelig, Davis M.
AU - Bhela, Siddheshvar
AU - Quarnstrom, Clare F.
AU - Fife, Brian T.
AU - Vezys, Vaiva
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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.
AB - 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.
KW - CD8 T cells
KW - Checkpoint
KW - Dysfunction
KW - Tolerance
KW - Tumor
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U2 - 10.1073/pnas.1810326116
DO - 10.1073/pnas.1810326116
M3 - Article
C2 - 30679280
AN - SCOPUS:85061369553
SN - 0027-8424
VL - 116
SP - 2640
EP - 2645
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -