Abstract PR-03: Competition for dendritic cells limits engineered TCR-T cell activation in tumor-draining lymph nodes and impairs synergy with PD-L1 blockade

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Abstract Adoptive transfer of engineered T cells has shown dramatic responses in blood cancers, but efficacy in more common solid tumors has been limited in part by poor persistence and T cell dysfunction. Studies of endogenous T cells in solid tumors have established that tumor-draining lymph nodes (TdLNs) harbor a population of stem-like PD-1+Tcf1+ progenitor exhausted T cells (Tpex) that can self-renew and continuously replenish functional T cells in tumors. Tpex in TdLNs are also the population that responds to PD-1/PD-L1 checkpoint blockade, highlighting the importance of TdLNs for T cell responses to solid tumors. It is not clear, however, whether engineered T cells form a similar stem-like Tpex population in TdLNs that can sustain effector T cell responses in the tumor or be enhanced by PD-L1 blockade. To test this, we adapted the Kras/p53 mouse model of lung cancer to express the TCR neoantigen ovalbumin (KPOva), enabling comparison of engineered T cells (TCR-T) and endogenous T cells (Endog-T) targeting the same tumor antigen. We activated Ova-specific OT-Is with anti-CD3/CD28 and expanded them in vitro with IL-2 and IL-15 to generate Ova-specific TCR-T cells, and we used SIINFEKL/H2-Kb tetramer to identify Ova-specific Endog-T cells. KPOva mice were left untreated or treated with cyclophosphamide (Cy) for lymphodepletion and infused with 1x106 OT-I TCR-T cells, mimicking clinical protocols. As expected, Endog-Ts preferentially accumulated in TdLNs and adopted a PD-1+Tcf1+ Tpex phenotype. TCR-Ts also preferentially accumulated in TdLNs; however, TCR-Ts showed reduced PD-1 upregulation compared to Endog-Ts, with many adopting a PD-1-Tcf1+ central memory phenotype, reflecting lack of activation. Interestingly, whereas Endog-Ts interacted with DCs in TdLNs at a ∼1:1 ratio, TCR-Ts swarmed DCs, forming clusters of 10-30+ cells. Cy treatment also depleted 70% of DCs in TdLNs, further skewing the TCR-T:DC ratio in the TdLN. We hypothesize that TCR-T compete for limited antigen presentation by DCs in TdLNs, impairing their upregulation of PD-1. Consistent with this hypothesis, infusion of 100-fold fewer TCR-Ts resulted in equivalent PD-1 upregulation in TdLNs as observed on Endog-Ts, indicating that reducing competition can restore TCR-T activation in TdLNs. Lastly, PD-L1 blockade boosted Endog-Ts in TdLNs and significantly improved tumor control, but PD-L1 blockade drove terminal differentiation of TCR-Ts in TdLNs and did not enhance TCR-T-mediated tumor control, showing that reduced PD-1 upregulation in TdLNs may limit TCR-T synergy with PD-L1 blockade. This study highlights that Cy followed by infusion of clinically relevant doses of TCR-Ts induces competition for DCs in TdLNs, potentially limiting TCR-T activation here and synergy with PD-1/PD-L1 blockade. Our work suggests that strategies to reduce competition, by selectively limiting TCR-T accumulation in TdLNs and/or boosting antigen-presentation by DCs in TdLNs, may sensitize TCR-T therapy to PD-L1 blockade and enable more effective control of solid tumors. Citation Format: Sam Nutt, Jessica Huang, Emma Bingham, Michael Gerner, Shivani Srivastava. Competition for dendritic cells limits engineered TCR-T cell activation in tumor-draining lymph nodes and impairs synergy with PD-L1 blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr PR-03.

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