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• W4308385289 abstract "<h3>Background</h3> Although failure to respond to checkpoint blockade immunotherapies is frequently associated with a lack of T-cell infiltration into the tumor, clinical data suggests that in patients with lung cancer, T-cell-inflamed tumors can also be resistant to therapy.¹ Work by us identified that checkpoint blockade immunotherapy resistance in T-cell-inflamed lung cancer is driven by lung cancer-specific CD8⁺ T-cell dysfunction, characterized by reduced cytolytic capacity and established during priming in the mediastinal lymph nodes (mLN).² In this study, we sought to uncover lung-specific mechanisms that blunt priming of anti-tumor cytotoxic T-cell responses. <h3>Methods</h3> To study T-cell priming against lung cancer, we implanted a syngeneic lung cancer cell line (KP) orthotopically in the lungs or subcutaneously in the flanks of C57BL/6 mice. Immune subsets were profiled using flow cytometry, immunofluorescence staining and RNA-sequencing. Immunological mechanism was dissected using adoptive T-cell transfers, bone marrow chimeras and <i>ex vivo</i> co-cultures. <h3>Results</h3> Both lung and flank KP tumors resulted in type-1-conventional dendritic cell (DC1)-dependent expansion of tumor-reactive T-cells, however, CD8⁺ T-cells primed in response to lung tumors in the mLN failed to upregulate key markers of effector CD8⁺ T-cell differentiation, namely CD25 and Granzyme B. Comparing DC1 from tumor-draining inguinal (iLN) and mLN revealed equivalent antigen load, but reduced expression of CD80, CD86 and IL-12 on mLN-derived DC1. Regulatory T-cell (Treg) depletion rescued both stimulatory molecule expression on DC1 and cytotoxic T-cell priming in the tumor-draining mLN, suggesting that lung CD8⁺ T-cell dysfunction required the local presence of Treg during priming. <i>Ex vivo</i> co-cultures validated that DC1 and Treg were required and sufficient to induce dysfunctional CD8⁺ T-cells. This immunosuppression was spatially coordinated within tissue-specific LN microniches and required antigen-specific contact between DC1 and Tregs, as abrogating MHCII-dependent Treg:DC1 interactions restored DC1 capacity to prime cytotoxic T-cell responses against lung tumors. The lung-specific suppression was associated with clonally expanded CXCR3⁺ T_H1-like effector Tregs, which were induced upon interferon sensing in the mLN. Consequently, interferon-gamma neutralization early during tumor induction could prevent the immunosuppression and restore cytotoxic T-cell priming in the mLN. Similarly, in cancer patients, interferon-sensing CXCR3⁺ Tregs but not CD8⁺/Treg ratios correlated with resistance to checkpoint blockade immunotherapy. <h3>Conclusions</h3> Our work suggests that the functional quality of Tregs, specifically the interferon-induced CXCR3⁺ T_H1-like effector state, rather than Treg quantity, is instrumental in restraining tumor-reactive T-cell responses and represents a critical barrier to productive anti-tumor immunity. <h3>Acknowledgements</h3> This work was supported by the Pew Stewart scholarship, the Koch Institute Frontier Research program, the Ludwig Center at MIT and the MIT School of Science Fellowship in Cancer Research. <h3>References</h3> Doroshow DB, Sanmamed MF, Hastings K, Politi K, Rimm DL, Chen L, Melero I, Schalper KA, and Herbst RS. Immunotherapy in non-small cell lung cancer: facts and hopes. <i>Clin Cancer Res</i> 2019;<b>25</b>:4592–602. Horton BL, Morgan DM, Momin N, Zagorulya M, Torres-Mejia E, Bhandarkar V, Wittrup KD, Love JC, Spranger S. Lack of CD8(+) T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. <i>Sci Immunol</i>. 2021;<b>6</b>:eabi8800. <h3>Ethics Approval</h3> All mouse experiments in this study were approved by MIT9s Committee on Animal Care (CAC) – DHHS Animal Welfare Assurance £ D16-00078." @default.
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• W4308385289 date "2022-11-01" @default.
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• W4308385289 title "1052 Tissue-specific interferon-gamma drives regulatory T-cells to restrain DC1-mediated priming of cytotoxic T-cells against lung cancer" @default.
• W4308385289 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1052" @default.
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