Postdoc Lerner Res. Inst., Cleveland Clin., Ohio, United States
Introduction/Rationale: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy driven by BRAFV600E. BRAF-targeted therapy is limited by drug resistance. Immune checkpoint blockade has shown promising outcomes to elicit antitumor immunity and improve the survival of patients. Our recent studies have identified leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a novel inhibitory receptor that suppresses T cell activation upon engaging with VISTA, a previously characterized immune checkpoint protein ligand.
Methods: WT, VISTA-KO (VPK), and LRIG1fl/fl CD4 Cre (LRIG1−/−) were used to orthotopically inoculate ATC231 thyroid cancer cells. CD8+ T cells were purified from spleen for co-adoptive transfer and chronically activated in vitro. Congenically marked WT (Thy1.1) and LRIG1−/− (CD45.1) OT1 T cells were co-transferred into naïve CD45.2 mice followed by ATC.OVA tumor inoculation. The extracellular flux assay along with mitochondria staining dyes were used to analyze the metabolic characteristics of T cells.
Results: LRIG1 deficiency reduced quiescent subset (TCF1+ CD62Lhi PD-1low) and led to a reciprocal increase in progenitor-like subset (TCF1+ PD-1+), expansion along with production of effector cytokines and Granzyme B. LRIG1-deficient T cells exhibited superior mitochondrial function and better energy production relative to WT T cells, which may support their improved expansion and function within tumor tissues. The improved T cell responses and tumor control were also observed in the VPK mice. Lastly, therapeutic treatment with a VISTA-specific monoclonal antibody that blocks the interaction between VISTA and LRIG1 improved the efficacy of PD-1 and CTLA-4 inhibitors and optimally reduced ATC tumor growth.
Conclusion: Taken together, these findings establish the VISTA/LRIG1 axis as a key immune checkpoint pathway and provide a strong rationale for targeting this axis for the treatment of ATC and potentially other malignancies that are resistant to current immunotherapies.
