Project 1: Targeting Tumor Phospholipase PLA2G10 for Cancer Immunotherapy

PROJECT 1: SUMMARY Only a small fraction of patients with non-small cell lung cancer (NSCLC) benefits from treatment with immune checkpoint blockers (ICB), and even patients who initially respond develop progressive disease. Immunologically cold tumors with features of T-cell exclusion (TCE) comprise a large fraction of NSCLCs, show aggressive clinical course and are resistant to immunotherapy. The biological determinants of TCE are poorly understood and effective treatments to counteract TCE in human malignancy are not available. Using functional screens for T- cell migration and cancer models, we identified the phospholipase PLA2G10 as a potent T-cell excluder upregulated in NSCLC. PLA2G10 increases the levels of lipid metabolites in the TME, is highly potent in suppressing the chemokine-induced migration of activated T-cells and has limited expression in non-tumor tissues. Based on these results, we hypothesize that tumor PLA2G10 upregulation is a dominant mechanism of adaptive immune resistance in NSCLC and a candidate therapeutic target for patients with immunologically cold tumors. We assembled a multidisciplinary team with complementary expertise to address 3 independent specific aims: 1) Aim 1: To determine the mechanisms of PLA2G10-mediated TCE in NSCLC; 2) Aim 2: To understand the clinical significance and immunomodulatory role of PLA2G10 in human NSCLC; and 3) Aim 3: To evaluate the impact of targeting PLA2G10 in cancer patients. Using an innovative and multi- modal approach including pre-clinical models, annotated NSCLC cohorts and a clinical trial, the proposed studies will expand the understanding of mechanisms underlying TCE and test strategies for effective targeting of PLA2G10-based TCE in patients with cancer.