Immune microenvironments of early onset vs late onset colorectal cancers

Abstract

Abstract Over the past 40 years, the incidence of rectal cancer in patients 20–39 years old has quadrupled. The immune microenvironment in colorectal cancer is a key player in disease progression, therapy response, and overall survival. However, the role of the immune microenvironment in early onset rectal cancer (less than 50 years old) has not been elucidated. We profiled the immune microenvironments of a cohort of early onset vs late onset (over 65 years) colorectal cancers from FFPE surgical specimens and biopsies from patients. We compared our dataset to a publicly available database (GSE8721) of gene expression profiles for 203 rectal cancer and 160 matched normal mucosa samples. We identified genes that were differentially expressed between early and late onset rectal cancer groups and validated our results with qPCR. Interestingly, we noted differences in immune signatures depending on the anatomical site (colon vs rectum). Two genes, FLT3 and SAA1, were found to have increased expression in both our patient samples and the GSE8721 rectal cancer database. FLT3 codes for fms-like tyrosine kinase receptor and activating mutations of this gene are present in 30% of acute myeloid leukemia cases and is associated with a worse prognosis. SAA1 codes serum amyloid A1 which is an acute phase protein that is highly expressed in response to inflammation. While FLT3 inhibitors did not directly affect tumor cell proliferation and cell death in vitro, we observed a decrease in tumor burden in vivo. Our data indicates that there are distinct changes in the immune microenvironment between early and late onset rectal cancer. We propose that understanding these changes will enable the development of age dependent immune modulation for this disease.