Human Gene and Microbial Analyses Suggest Immunotherapy-like Mechanisms in Complete Response to Radiotherapy in Rectal Cancer

Abstract

The treatment of rectal cancer usually involves total mesorectal excision, with preoperative chemoradiotherapy (CRT) that is aimed at downstaging tumors before surgical procedure. CRT response varies, with some patients completely responding to CRT and negating the need for surgery, and some patients not responding to the treatment at all. Identifying biomarkers of response to CRT would be beneficial in identifying whether a treatment would confer benefits to a patient while allowing them to avoid unnecessary morbidities and mortalities. While previous studies have attempted to identify such biomarkers, none have reached clinical utility which may be due to heterogeneity of the cancer. In this paper, we explored potential human gene and microbial biomarkers, and their possible contributions to the mechanisms of complete response to chemoradiotherapy. We carried out RNA sequencing on pairs of tumor and normal tissue from patients pre-surgery and analysed host gene expression and microbiome content. We discovered that the majority of enriched human genes in tumors of complete responders involve immunoglobulins, and enriched gene sets include complement and B-cell activation, and host response against viruses. This indicates involvement of immune responses in complete response to CRT. Among the enriched gene sets is the term defense response to bacterium, indicating a role of the microbiome in response to CRT. We discovered bacteria such as Ruminococcaceae bacterium and Bacteroides thetaiotaomicron to be abundant in tumors of complete responders. Both microbes have a history of being beneficial in treatment of cancers with immunotherapy, further emphasizing the role of immune responses in beneficial response to CRT. These results identify potential genetic and microbial biomarkers to CRT in rectal cancer, as well as offer a potential mechanism of complete response to CRT that may benefit further testing in the laboratory.