Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis

By A. Schietinger, M. Philip, Varintra E. Krisnawan, E. Chiu, J. Delrow, Ryan S. Basom, P. Lauer, D. Brockstedt, S. Knoblaugh, G. Hämmerling and 3 more. Immunity, 2016

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SUMMARY 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/3c71b1e68f86aee035ffd7f8aa47fc65dff94efc

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Citations in the corpus

Dysfunctional CD8+ T cells form a proliferative, dynamically regulated compartment within human melanoma (2018, background): “In murine models, T cells with high expression of markers of T cell exhaustion appear refractory to reinvigoration by PD-1 blockade (Blackburn et al., 2008; Im et al., 2016; Pauken et al., 2016; Philip et al., 2017; Schietinger et al., 2016).”
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade (2018, methodology): “…was used to determine whether predefined exhaustion gene sets showed enrichment in the PD-1T and PD-1N subsets (Crawford et al., 2014; Schietinger et al., 2016, Gupta et al., 2015, Quigley et al., 2010, Zheng et al., 2017, Doering et al., 2012, Baitsch et al., 2011, Tirosh et al.,…”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Indeed, tumor-specific CD8 T cells display hallmarks of T cell exhaustion and dysfunction in mouse models (24, 25) and human cancers including, but not limited to, melanoma (26–30), chronic myeloid leukemia (24), ovarian cancer (31), non–small cell carcinoma (32, 33), Hodgkin lymphoma (34), and chro”
T Cell Dysfunction in Cancer (2018, background): “This notion is further supported by the observation that a fixed state of dysfunction was only induced in tumor-specific T cells, when tumor-specific and bystander T cells were co-transferred in a murine liver cancer model (Schietinger et al., 2016).”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “For example, disease-related dysfunctions of T cells 217 , such as those described in patients with CLL 218,219 or solid tumours 220 , can result in unsuccessful manufacturing or inferior products that lead to poor response rates in patients.”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “Studies indicate that T cells acquire characteristics of exhaustion early in tumorigenesis and that, in advanced states, the exhaustion is irreversible (Schietinger et al., 2016).”