PhD Candidate Lerner Res. Inst., Cleveland Clin. Cleveland, Ohio, United States
Disclosure(s):
Paolo Elguera: No financial relationships to disclose
Introduction/Rationale: VISTA is a myeloid-enriched inhibitory ligand strongly linked to poor therapeutic outcomes in triple-negative breast cancer (TNBC). However, the mechanism by which VISTA suppresses CD8⁺ T cell immunity has remained unclear. We recently identified LRIG1 as a T cell–intrinsic binding partner for VISTA. Here, we investigate how the VISTA–LRIG1 axis contributes to immune resistance in TNBC using genetic mouse models, tumor immunophenotyping, and integration of clinical datasets.
Methods: We used global VISTA knockout (VISTA KO) mice and Granzyme B–Cre LRIG1 conditional knockout (GzmB-Cre LRIG1 KO) mice in the E0771 TNBC model. Tumors were analyzed by flow cytometry, and cytokine profiling. Myeloid signatures from VISTA-deficient cells were compared to breast cancer patient datasets. Public single-cell TNBC data (Zhang et al., 2021) and a neoadjuvant chemotherapy cohort were used to assess clinical correlations with VISTA expression.
Results: VISTA KO mice exhibited significantly improved control of E0771 tumors, along with reduced suppressive myeloid programs and increased tumor-infiltrating CD8⁺ T cells. The VISTA-deficient myeloid signature correlated with improved survival across breast cancer datasets. Clinically, VISTA was enriched in myeloid cells from TNBC non-responders to PD-L1 blockade and associated with higher residual cancer burden following chemotherapy. GzmB-Cre LRIG1 KO mice displayed enhanced tumor control driven by increased CD8⁺ T cell proliferation, reduced quiescence, greater cytokine production, and expansion of TCF1⁺ progenitor-like subsets.
Conclusion: The VISTA–LRIG1 axis functions as an integrated suppressive pathway across myeloid and T cell compartments in TNBC. Genetic disruption of either VISTA or LRIG1 improves CD8⁺ T cell function and tumor control. These findings establish this axis as a key driver of immune resistance and a promising target for therapeutic intervention
