Abstract LB123: TIGIT and PD-L1 co-blockade activates type 1 conventional dendritic cells to promote non-exhausted anti-tumor CD8+ T cell immunity through enhanced costimulation

Abstract Background: Dual inhibition of the PD-1 and TIGIT checkpoint receptor pathways has demonstrated synergistic anti-tumor activity in preclinical studies and early clinical trials, but its mechanism(s) of action remains incompletely understood. We now know that PD-1 and TIGIT regulate CD28 and CD226 costimulatory signals and thus co-blockade presents a rational strategy to facilitate the transmission of these activating signals to T cells. However, therapeutic efficacy of the combination is contingent upon a functional anti-TIGIT Fc domain, thereby implicating a role for myeloid cells, which abundantly express Fc receptors (FcR). Here, we aimed to delineate the relevant myeloid cells at play and investigate how they facilitate improved anti-tumor CD8+ T cell responses during PD-1 and TIGIT co-blockade therapy. Methods: We compared the tumor immune infiltrate from wild-type or genetically modified mice treated with anti-PD-L1 in combination with either Fc-active mIgG2a anti-TIGIT (‘Combo-mG2a’) or Fc-inert mIgG2a-LALAPG anti-TIGIT (‘Combo-LALAPG’). Flow cytometry and single-cell RNA-sequencing were used for cell profiling. Antibody blocking studies and in vitro co-culture assays were performed to confirm in vivo results. Results: Tumor-bearing mice treated with Combo-mG2a were able to robustly control their tumors compared to their Combo-LALAPG-treated counterparts. We uncovered a requirement for type 1 conventional dendritic cells (cDC1) during Combo-mG2a treatment administration for anti-tumor efficacy and non-exhausted CD8+ T cell programming. Transcriptional profiling and immunophenotyping studies revealed a cDC1 activation state enriched in Combo-mG2a tumors marked by FcR expression and upregulation of the costimulatory ligands CD80/CD86 and PVR (termed ‘FcR+ cDC1’). The receptors for these ligands, CD28 and CD226, respectively, were co-expressed by therapy-responsive CD8+ T cells, with only CD226 being strongly upregulated following Combo-mG2a therapy. CD8+ T cell-intrinsic CD226 signaling was essential for non-exhausted T cell differentiation. Despite the widespread expression of PVR, cDC1-specific PVR expression was critical for maximal therapeutic efficacy of TIGIT and PD-L1 combination blockade. Type-I interferon (IFN-I) administration was sufficient to induce the FcR+ cDC1 state to rescue anti-tumor immunity in Combo-LALAPG tumors, highlighting IFN-I as a key downstream component of FcR engagement in Combo-mG2a tumors that activated cDC1. Conclusions: Our study identifies cDC1-facilitated costimulation as a critical factor in the therapeutic efficacy of TIGIT and PD-L1 combination blockade. Mechanistic insights from this work can inform the design of new therapeutic strategies to increase immunotherapy responses. Citation Format: Ellen Duong, Thomas D. Wu, Karl Banta, Katie Nutsch, Charles Tran, Milena Hornburg, Eugene Y. TIGIT and PD-L1 co-blockade activates type 1 conventional dendritic cells to promote non-exhausted anti-tumor CD8+ T cell immunity through enhanced costimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB123.