Glucocorticoids Mediate Faulty Tumor-Infiltrating Lymphocyte Function

Dysfunctional CD8⁺ T cells in the tumor microenvironment (TME) have poor cytotoxicity and produce immunosuppressive chemicals such as the cytokine IL10. In models of mouse colon carcinoma and human melanoma, Acharya, Madi, and colleagues found increasing expression of glucocorticoid receptor (GR) in CD8⁺ tumor-infiltrating lymphocytes (TIL) as they approached terminal dysfunction, with TIM3⁻PD⁻ cells having low expression, TIM3⁻PD-1⁺ cells having intermediate expression, and TIM3⁺PD-1⁺ cells having high expression. Single-cell RNA sequencing of CD8⁺ TILs from melanoma verified the observed gradient of low–glucocorticoid (GC) signature cells to high–GC signature cells, and the low–GC signature cells highly expressed naïve T-cell genes, whereas the high–GC signature cells highly expressed effector and dysfunction genes. Repeated CD8⁺ T-cell activation in the presence of a synthetic or natural GC (dexamethasone or corticosterone, respectively) led to reduced production of the proinflammatory cytokines IL2, TNFα, and IFNγ and increased production of the immunosuppressive cytokine IL10 as well as PD-1, TIM3, and LAG3. In vivo, deficiency of Nr3c1 (encoding GR) hindered tumor growth in multiple models, and CD8⁺ TILs from Nr3c1-deficient mice had greater responses to tumor-antigen and polyclonal stimulation, producing more IL2, TNFα, and IFNγ. These TILs were also more cytotoxic, becoming granzyme B⁺CD107a⁺ upon tumor-antigen stimulation, produced less IL10, and had reduced coexpression of PD-1, TIM3, LAG3, and TIGIT. Tumor antigen–specific CD8⁺ TILs from the Nr3c1-deficient mice also had lower expression of the transcription factor TCF1, which regulates effector T-cell differentiation. Mechanistically, GC signaling transactivated expression of checkpoint receptors and IL10 and directly induced genes linked to T-cell dysfunction. The source of GC in the TME was found to be monocyte–macrophage-lineage cells. Finally, elevated GC signaling was correlated with lack of response to immune-checkpoint blockade in mouse models and patients with melanoma. In summary, this work elucidates the role of GC signaling in regulating T-cell function in the TME, providing insight into how TILs become dysfunctional over time.

Acharya N, Madi A, Zhang H, Klapholz M, Escobar G, Dulberg S, et al. Endogenous glucocorticoid signaling regulates CD8⁺ T cell differentiation and development of dysfunction in the tumor microenvironment. Immunity 2020;53:658–71.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.