Session 2:  Microenvironment and resistance 

Harnessing gut immunity to target metastases

Among the anti-cancer therapeutic options, immunotherapy has led to clinical benefit in several malignancies. However, many metastatic colorectal cancer (mCRC) patients remain largely unresponsive to immunotherapy. The gut, where primary tumors are located, is a unique barrier organ, comprising locally-primed T lymphocytes. Gut immunity is regulated by several intestinal components, including the microbiota. We recently uncovered that primary colon tumors are able to prime tumor-specific CD8 T cells, which are endowed with superior anti-tumor abilities compared to non-intestinal CD8 T cells. While gut immunity was previously thought to be locally confined, we described that, during mCRC, enterotropic CD8 T cells emigrate from the gut and infiltrate extra-intestinal metastases, where they promote response to immunotherapy and mediate metastases elimination. Currently, we aim to apprehend the therapeutic potential of intestinal anti-tumor CD8 T cells in controlling mCRC metastases. We are conducting an in depth characterization of colon tumor-primed CD8 T cells, in the preclinical setting, investigating the factors that regulate their activation, including the microbiota, as well as the kinetics and magnitude of their trafficking. In addition, we are monitoring proportions of circulating intestinal CD8 T cells, in both preclinical and clinical settings, to assess their potential as biomarkers of metastasis outcome. Finally, we are developing a therapeutic strategy specifically designed to elicit intestinal CD8 T cells. Our work may lead to 1) identifying the potential of intestinal CD8 T cells as novel biomarkers for responsive tumor types; and 2) evaluating strategies to elicit tumor-specific intestinal CD8 T cells in the context of immunotherapy-resistant tumors.