A distinct innate immune signature of early onset colorectal cancer Authors: Ivy H. Gardner MD1, Ragavan Siddharthan MD1, Katherine Watson MD1, Elizabeth Dewey MS1, Rebecca Ruhl BS2,3, Xiangnan Guan PhD3,4,5, Zheng Xia PhD3,4,5, Liana V. Tsikitis MD, MCR, MBA1,3#, and Sudarshan Anand PhD2,3,6# 1. Department of Surgery, 2. Department of Cell, Developmental and Cancer Biology, 3. Knight Cancer Institute, 4. Department of Molecular Microbiology & Immunology, 5. Computational Biology Program, 6. Department of Radiation Medicine, Oregon Health & Science University, 2720 S. Moody Avenue, Portland, OR Corresponding Author: Sudarshan Anand PhD 2720 S. Moody Avenue, KCRB 3004 Portland, OR 97201 503-494-8043 firstname.lastname@example.org # These authors contributed equally Abstract Purpose: Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (50 years old) and late onset (65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. Experimental Design: We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. Results: We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Conclusion: Our data demonstrate that the immune microenvironment is characterized by a distinct innate immune response signature in early onset CRC that is unique, location dependent, and associated with worse outcomes.