Lymph Node–Specific IFNγ Levels Affect CD8⁺ T-cell Priming against Tumors

Though it is known that the microenvironment can affect tumor antigen–specific T-cell activation, the mechanisms by which this occurs remain unclear. Zagorulya and colleagues investigated how the different environments of tumor-draining lymph nodes (tdLN) affect CD8⁺ T-cell responses in lung cancer. Lung adenocarcinoma cells were injected into the lungs of mice, and antigen-specific T-cell activation was measured in the mediastinal lymph nodes (mLN) and inguinal lymph nodes (iLN), tdLNs for the chest and groin, respectively. Although similar levels of antigen-specific T cells accumulated, those primed in the mLN exhibited lower expression of effector molecules than those in the iLN. Functional cytotoxic T cells failed to form in mice lacking type 1 conventional dendritic cells (DC1), suggesting that DC priming of CD8⁺ T cells is needed in both tdLNs, but mature DC1 cells in the mLN expressed lower levels of T-cell stimulatory signals, indicating altered cytotoxic T-cell priming in the mLN. Further investigation revealed that effector T-cell function could be restored in mice lacking regulatory T cells (Treg), suggesting that Tregs suppress DC1-mediated CD8⁺ T-cell priming and differentiation in the mLN. Specifically, Tregs isolated from the mLN inhibited the expression of DC1 stimulatory signals through major histocompatibility complex class II–mediated physical contact, leading to the generation of dysfunctional CD8⁺ T cells. Evaluation of tissue-specific factors that mediate these Tregs indicated that those from the mLN expressed genes involved in Treg to T helper 1 (Th1) polarization, IFN response, and immunosuppression. Additionally, depletion of IFNγ signaling reduced Th1 polarization of Tregs and increased CD8⁺ T-cell responses in the mLN. Finally, Th1 polarization of Tregs correlated with immunotherapy resistance in patients with melanoma. Altogether, these results show a generalizable immune tolerance mechanism by which differential IFNγ expression in the tdLNs affects the activation of tumor-specific T cells.

Zagorulya M, Yim L, Morgan DM, Edwards A, Torres-Mejia E, Momin N, et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 2023;56:386–405.

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