The responder/nonresponder phenomena: The immune system’s role in determining the outcome of radiation therapy in rectal cancer

Abstract

Abstract While surgical resection is a viable option to treat patients with rectal cancer (RC), it is not without significantly reducing patients’ quality of life. In an effort to delay or even prevent surgery, patients are often administered pre-operative radiation therapy (RT). Although RT can significantly reduce tumor burden in a subset of patients, there are many patients whose tumors do not respond to RT. To study this, we developed an orthotopic model of RC that recapitulates human disease in which administration of clinically relevant RT results in mice bearing tumors that demonstrate a reduction of tumor burden (responders), and a group of animals whose tumors respond poorly (nonresponders). RNA-sequencing of intratumoral immune populations identified a unique gene signature associated with each group. Tumor-associated macrophages (TAMs) from nonresponding tumors were more similar to TAMs from untreated tumors when compared to TAMs from responding tumors. Interestingly, TAMs in responding tumors upregulate pathways associated with pattern recognition receptor signaling and damage associated molecular patterns. These data suggest that TAMs from responding tumors may be polarized to respond to the immunostimulatory damage induced by RT. While TAM polarization plays a large role in promoting either an immunostimulatory or immunosuppressive microenvironment, CD8+ T cells are directly responsible for killing tumor cells. We sequenced intratumoral CD8+ T cells as well and determined that T cells from responding tumors induced pathways consistent with enhanced effector function. These data suggest that a targeted therapy aimed at the TAM:CD8+ T cell interaction may promote a stronger RT response in the nonresponding tumors.