A gut feeling about Complement in Early Onset Colorectal Cancer

Abstract

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States, with a significant increase in incidence observed in young adults below the screening age. We hypothesized that differences in the immune tumor microenvironment (TME) between early-onset (≤50 years) and late-onset (≥65 years) CRC drives tumor progression and responses to treatment. Our studies in a cohort of 121 patients indicate that complement pathway genes including C7 and Complement Factor D (CFD) and the anti-apoptotic gene Bcl2 are significantly increased in early onset CRC vs late onset disease. Moreover, the immune genes in this signature also correlate with progression free survival in our cohort. Analyses of this signature in an independent TCGA cohort also shows association of these genes with progression free survival. Surprisingly, tumor intrinsic CFD gain of function experiments in preclinical mouse tumor models increased tumor burden and recapitulated a subset of the early onset human immune gene signature. Inhibition of CFD, in combination with a Bcl2 inhibitor, significantly decreased clonogenic survival in human CRC lines in vitro. Our data associates a distinct complement enhanced immune microenvironment and hints at a putative role for the microbiome in shaping this immune microenvironment in younger patients with more aggressive disease. Taken together, our work highlights complement and the innate immune response as a potential contributor to early onset CRC. Supported by grants from NIH to SA (R01 HL137779 and R01 HL143803)