TY - JOUR
T1 - Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis
AU - Schietinger, Andrea
AU - Philip, Mary
AU - Krisnawan, Varintra E.
AU - Chiu, Edison Y.
AU - Delrow, Jeffrey J.
AU - Basom, Ryan S.
AU - Lauer, Peter
AU - Brockstedt, Dirk G.
AU - Knoblaugh, Sue E.
AU - Hämmerling, Günter J.
AU - Schell, Todd D.
AU - Garbi, Natalio
AU - Greenberg, Philip D.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016
Y1 - 2016
N2 - CD8+ T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8+ T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.
AB - CD8+ T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8+ T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.
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U2 - 10.1016/j.immuni.2016.07.011
DO - 10.1016/j.immuni.2016.07.011
M3 - Article
C2 - 27521269
AN - SCOPUS:84994330192
SN - 1074-7613
VL - 45
SP - 389
EP - 401
JO - Immunity
JF - Immunity
IS - 2
ER -