Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.
Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.
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DOI：
10.1016/j.immuni.2016.07.011
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发表时间：
2016-08-16
期刊：
影响因子：
32.4
通讯作者：
Greenberg, Philip D.
中科院分区：
文献类型：
--
作者：
Schietinger, Andrea;Philip, Mary;Krisnawan, Varintra E.;Chiu, Edison Y.;Delrow, Jeffrey J.;Basom, Ryan S.;Lauer, Peter;Brockstedt, Dirk G.;Knoblaugh, Sue E.;Haemmerling, Guenter J.;Schell, Todd D.;Garbi, Natalio;Greenberg, Philip D.
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. Tumor-specific CD8+ T cells found in human solid tumors are often dysfunctional, but when and how during tumorigenesis this T cell dysfunction arises was not known. Schietinger and colleagues show that CD8+ T cells become dysfunctional early during tumorigenesis at the pre-malignant stage through an antigen-driven dynamic differentiation program.
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. Tumor-specific CD8+ T cells found in human solid tumors are often dysfunctional, but when and how during tumorigenesis this T cell dysfunction arises was not known. Schietinger and colleagues show that CD8+ T cells become dysfunctional early during tumorigenesis at the pre-malignant stage through an antigen-driven dynamic differentiation program.
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