Project Summary Immune checkpoint blockade (ICB) therapy has demonstrated significant clinical benefit in late-stage patients with melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, bladder cancer, non-small cell lung cancer, gastric cancer, liver cancer, cervical cancer, Merkel cell carcinoma, and for all microsatellite- unstable tumors. A major limitation of ICB therapies targeting the CTLA4 or PD1 immune checkpoints is that a significant portion of patients will experience immune-related adverse events (irAEs), which can result in permanent or even fatal toxicity and discontinuation of life-saving immunotherapy. Compounding this problem is the fact that there currently exist no molecular modulators for ICB-driven irAEs. This R01 application examines circulating LPC 18:2 a novel small molecule modulator and therapeutic for irAEs by studying human cancer patients and relevant preclinical models of ICB-driven irAEs and tumor regression. The proposed aims will systematically i) examine association between LPC 18:2 and irAEs across multiple human cancer cohorts (e.g. melanoma, non small lung cancer, head and neck squamous cell carcinoma) and ICB therapies (e.g. anti- CTLA4 ipilimumab, anti-PD1 pembrolizumab and combination therapies); ii) examine relationship between plasma LPC 18:2 levels and ICB-driven tumor regression or natural autoimmune disease; iii) study the immunological mechanisms by which LPC 18:2 restrains ICB-driven irAEs and autoimmune colitis; iv) mechanistically probe novel effects of LPC 18:2 and LPC-G2A signaling on development and function of inflammatory neutrophils. This study uses a highly innovative approach leveraging cancer patient bio-sampling across multiple independent clinical trials with state-of-the-art rapid mass spectrometry profiling of small molecule metabolites and mechanistic studies. This is a collaborative study between a cancer immunologist and basic scientist at La Jolla Institute for Immunology and UCSD Moores Cancer Center, an analytical chemist at UCSD, a statistical epidemiologist at Cedars-Sinai Medical Center, clinical immune-oncology collaborators and experts on fundamental immunology and neutrophils. Validating LPC 18:2 as a therapeutic molecule for irAE toxicities addresses an urgent need at the clinical level to develop the very first therapies that can minimize risk, maximize benefit, and more accurately personalize ICB therapies for those patients who stand to benefit from cancer immunotherapy.