Project Grant F30CA310083

TARGETING SIALYLATION AS A NOVEL GLYCOIMMUNE CHECKPOINT IN SMALL CELL LUNG CANCER - PROJECT SUMMARY / ABSTRACT SMALL CELL LUNG CANCER (SCLC) IS A HIGHLY LETHAL SUBTYPE OF LUNG CANCER WITH NO CURRENT CURE AND LIMITED TREATMENT OPTIONS PROLONGING PATIENT SURVIVAL BEYOND ONE YEAR. IN 2019, ANTI-PDL1 ANTIBODY THERAPY WAS ADDED TO COMBINATORIAL PLATINUM-ETOPOSIDE CHEMOTHERAPY AS THE NEW STANDARD OF CARE AFTER TWO INDEPENDENT CLINICAL TRIALS DEMONSTRATED IMPROVED SURVIVAL IN PATIENTS WITH EXTENSIVE STAGE DISEASE, MARKING THE FIRST APPROVED USAGE OF IMMUNOTHERAPIES IN TREATING SCLC. HOWEVER, THE OBSERVED CHANGE IN SURVIVAL HAS ONLY BEEN MODEST (A FEW MONTHS), AND DISEASE RELAPSE ULTIMATELY OCCUR FOR MOST PATIENTS. UNSURPRISINGLY, THE TUMOR IMMUNE MICROENVIRONMENT OF SCLC HAS BEEN CHARACTERIZED AS HIGHLY IMMUNOSUPPRESSIVE, LIKELY CONTRIBUTING TO THE LACK OF EFFECTIVE AND PROLONGED RESPONSES TO IMMUNOTHERAPIES. THUS, THERE REMAINS A CRITICAL NEED TO EXPLORE AND IMPROVE IMMUNOTHERAPEUTIC APPROACHES IN SCLC. THIS PROJECT PROPOSES INVESTIGATING AND TARGETING SIALIC ACID, A SUGAR MOLECULE OVEREXPRESSED IN NUMEROUS CANCERS, AS A NOVEL GLYCO-IMMUNE CHECKPOINT TO IMPROVE ANTI-TUMORAL IMMUNE RESPONSES. SEVERAL STUDIES IN OTHER MALIGNANCIES HAVE SHOWN THAT CANCER CELLS CAN HIJACK THIS AXIS AS A MECHANISM OF IMMUNE EVASION THROUGH INTERACTIONS AND SIGNALING WITH THE SIGLEC FAMILY OF INHIBITORY RECEPTORS ON INFILTRATING IMMUNE CELLS. IN SCLC, HYPERSIALYLATION AND SIGLEC SIGNALING REMAIN COMPLETELY UNSTUDIED. AIM 1 OF THIS PROPOSAL WILL TEST IF AND HOW INDUCED LOSS OF ENDOGENOUS SIALYLATION, USING GENETICALLY PERTURBED MOUSE MODELS OF SCLC AND PATIENT DERIVED XENOGRAPHS, LEADS TO INCREASED ANTIGENICITY AND IMMUNOGENICITY. USING IN VIVO SYNGENEIC MOUSE MODELS, AIM 2 WILL INVESTIGATE IF TUMOR DESIALYLATION CAN MODIFY THE IMMUNOSUPPRESSIVE MICROENVIRONMENT OF SCLC TO BECOME MORE REACTIVE AND WILL ALSO ASSESS FOR SYNERGY WITH CURRENT STANDARD OF CARE ANTI-PD1 IMMUNE CHECKPOINT BLOCKADE THERAPY. TAKEN TOGETHER, THE WORK PERFORMED IN THIS PROPOSAL WILL IMPROVE OUR UNDERSTANDING OF THE MECHANISMS BEHIND IMMUNE RESPONSES IN SCLC AND POTENTIALLY UNCOVER A NOVEL IMMUNOTHERAPEUTIC APPROACH FOR TREATING SCLC IN HOPES OF IMPROVING TREATMENT OPTIONS FOR THIS AGGRESSIVE DISEASE.