855 LRIG1 engages ligand VISTA to impede T cell activation and enable tumor immune evasion

• DOI: 10.1136/jitc-2024-sitc2024.0855
• Publication Date: 2024-11-05T14:58:59Z
• Authors: Hieu M Ta; Dia Roy; Keman Zhang; Tyler Alban; Ivan Juric; Prerana Parthasar...; Juan Dong; Sachin Patnaik; Elizabeth Delaney; Amin Zakeri; Nidhi Shukla; Amit Rupani; Yee Phoon; Stefanie Avril; Brian Gastman; Timothy Chan; Li Wang
• Keywords: Evasion (ethics)

<h3>Background</h3> Immune checkpoint blockade represents a promising strategy to activate anti-tumor immunity and improve the survival of patients with cancer. Recent studies have established role 'stem-like' tumor-specific CD8⁺ T cells that express TCF-1 respond ICI therapies by exiting quiescent states proliferative burst. On other hand, mechanisms maintain quiescence TCF-1⁺ stem-like not been well understood may underlie clinical resistance current immunotherapies. VISTA is an emerging immune target, yet its downstream signaling pathways remain elusive. <h3>Methods</h3> To identify VISTA-binding receptors, we performed selective proteomic labeling proximity ligation assay using tyramide in conjunction mass spectrometry analysis activated splenic cells. validate interaction between LRIG1 (LV) <i>in-vitro</i> <i>in-vivo</i>, employed SPR, Co-IP Luciferase-based binding assay. dissect outcomes LV interaction, proximal TCR murine cell line expressing were examined. understand inhibitory toward activation, WT <i>Lrig1^-</i>^/- OT1 stimulated impact deletion immunity, <i>Lrig1-</i>/- mice challenged different tumor models. molecular characteristics persistent CTLs heterogeneity TILs context deficiency, from subjected single-cell transcriptomic profiling. <h3>Results</h3> We as novel partner (figures 1,2), which acts receptor suppress upon engagement (figure 3). <i>Lrig1</i>^-/- demonstrated resistant suppressing effect <i>cis/trans</i>-VISTA 4). The CD28–PI3K–AKT–mTOR pathway was up-regulated LRIG1-deficient cytotoxic lymphocytes (CTLs), resulting improved expansion, survival, effector function 5). Mice cell–specific developed superior responses 6). Sustained control associated decrease (TCF1⁺ CD62L^hi PD-1^low) reciprocal increase progenitor memory-like PD-1⁺) 7). antibody treatment effectively enhanced showed therapeutic efficacy against B16 melanoma E0771 triple-negative breast cancer model 8). In human melanoma, high expression on tumor-infiltrating correlated immunotherapies 9). <h3>Conclusions</h3> These findings delineate provide rationale for targeting VISTA/LRIG1 axis immunotherapy 10).