Interaction between T-cell inflamed gene expression profile score and tumor-associated microbiome on colorectal cancer mortality in a heterogeneous patient population

Background: The microbiome and tumor immune response are important and inter-related components that are implicated in colorectal cancer (CRC) prognosis. However, associations between these components and potential joint effects on CRC mortality remain unclear. Methods: We included 366 participants with CRC (106 African American, 161 Alaska Native, 91 Hispanic, 8 non-Hispanic White) from the Translational Research Program in Cancer Differences across Populations (TRPCDP). 241 participants who did not die of CRC were matched to 125 participants who died of CRC during follow-up by age, sex, tumor site, tumor stage, year of diagnosis, and population group. We sequenced microbial DNA from the V4 region of the 16S rRNA bacterial gene and sequenced RNA using the Illumina TruSeq RNA Exome kit from formalin-fixed paraffin embedded (FFPE) tumor tissue. We calculated the T-cell inflamed gene expression profile (GEP) score as a weighted sum of log 2 -transformed transcripts per million of 18 genes: CCL5, CD27, CD274 (PD-L1), CD276 (B7-H3), CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PDCD1LG2 (PDL2), PSMB10, STAT1, and TIGIT. We dichotomized the T-cell inflamed GEP score into high and low groups using the top tertile as a threshold. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between bacterial presence and dichotomized T-cell inflamed GEP score, as well as interaction effects of bacteria and dichotomized T-cell inflamed GEP score on CRC-specific mortality, adjusting for matching factors. Results: Among 48 genera tested, Anaerococcus was associated with lower odds of high T-cell inflamed GEP score (OR=0.34, 95% CI 0.20-0.58) and Leptotrichia was associated with higher odds of high T-cell inflamed GEP score (OR=2.93, 95% CI 1.66-5.22). When combined, the joint effect of tumors being Leptotrichia positive and low T-cell inflamed GEP score was associated with over four times the odds of CRC mortality (OR=4.41, 95% CI 1.86-10.83) compared to tumors that were Leptotrichia negative and high T-cell inflamed GEP score. Conclusions: The joint effect of Leptotrichia presence and low T-cell inflamed GEP score resulted in markedly higher odds of CRC death. Understanding the influence of this immune-microbiota interaction may improve CRC prognostic stratification and enable the discovery of new treatment targets to improve CRC prognosis.