Distant antimetastatic effect of enterotropic colon cancer-derived a4ß7 CD8 T cells [bulk RNA-seq]

Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic a4ß7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of a4ß7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients' cohort, we show increased expression of genes encoding the a4ß7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating a4ß7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific a4ß7+ CD8 T cells. Overall design: Bulk RNA sequencing was performed on 17 human metastatic samples (from a MSS (MicroSatellite Stable profile) metastatic CRC cohort).