Distant antimetastatic effect of enterotropic colon cancer-derived α4β7+CD8+T cells

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 metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic alpha 4 beta 7 integrin-expressing neoantigen-specific CD8 T cells were key compo-nents of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti-PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of alpha 4 beta 7+ cells abrogated control of metastases. Last, in patients with metastatic CRC, response to ICB was associated with expression of alpha 4 beta 7 integrin in metastases and with circulating alpha 4 beta 7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor -spe-cific alpha 4 beta 7+ CD8 T cells.

Automated summary

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 metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic alpha 4 beta 7 integrin-expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Our findings identify a systemic cancer immunosurveillance role for gut-primed tumor-specific alpha 4 beta 7+ CD8 T cells.