靶向唾液酸化促进小细胞肺癌的抗肿瘤免疫

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with a 5-year relative survival rate of less than 10%, even with the addition of immune checkpoint blockade to standard of care therapy. The tumor immune microenvironment of SCLC has been characterized as highly immunosuppressive, and SCLC suppresses the expression of antigen presentation machinery, likely contributing to the lack of effective prolonged immunotherapy responses. Our project investigates the targeting of sialic acid, a sugar molecule overexpressed in many cancers, to increase anti-tumoral immune responses. Studies in other malignancies have shown that cancer cells can hijack this axis as a mechanism of immune evasion through interactions with the SIGLEC family of inhibitory receptors on infiltrating immune cells. We hypothesize that SCLC also utilizes sialic acids for immune masking, and that tumor desialylation would improve anti-tumor responses and could be a potential novel therapeutic approach for SCLC. Using SCLC lines that we derived from genetically engineered mouse models harboring Rb1/Trp53 inactivation, we performed genome wide CRISPR deletion screens and identified Gne as a top gene regulating SCLC sialylation. We then deleted Gne and confirmed robust decreases in sialylation. Under interferon-y stimulated conditions, Gne -deleted cells exhibited elevated MHC-I expression and IFNy signaling pathway, suggesting that loss of sialylation leads to increased antigen presentation and intrinsic immunogenicity. These results are relevant as recent clinical data revealed SCLC patients with low MHC-I expression respond poorer to anti-PDL1 therapy. When the Gne -deleted cells were propagated into mice as flank tumors or as a disseminated metastatic model, we observed delayed tumor kinetics and prolonged survival in syngeneic immunocompetent hosts, but not in immunocompromised recipients, suggesting that the observed effects are immune dependent. Immunophenotyping of syngeneic tumors by flow cytometry revealed increased tumor MHC-I expression and higher infiltration of tumor antigen specific CD8+ T cells upon Gne deletion. Furthermore, co-culturing of Gne -deleted cells expressing ovalbumin with ovalbumin antigen (OT-I) specific CD8+ T cells showed increased tumor cell killing and T cell activation. Lastly, analysis of patient SCLC samples in the IMpower133 clinical trial revealed a survival benefit with chemo-immunotherapy for patients expressing lower transcriptional levels of key sialic acid biosynthesis genes, while this effect is absent in the chemotherapy only group. Altogether, our data suggests that desialylation improves immunogenicity and anti-tumor immunity in SCLC. Ultimately, our work improves the understanding of the mechanisms behind immune responses in SCLC and has potentially uncovered a novel glyco-immunotherapeutic approach to develop new treatments for SCLC in the clinical setting.