The VISTA—LRIG1 Axis Integrates Myeloid and T Cell Suppression to Drive Immune Resistance in Triple-Negative Breast Cancer 2303786

Abstract

Abstract Introduction 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 Funding Source NIH, CDMRP and MRF Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)