The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Feliu, V., Gomez-Roca, C. et al. Science Immunology. 8 (84): eadg8841 (2023).
doi: 10.1126/sciimmunol.adg8841.
Summary of the findings
In metastatic colorectal cancer (mCRC), metastases are resistant to treatment, thus representing a pivotal challenge for therapy improvement. In addition, the gut immune response develops locally, for instance with the priming of CD8 T lymphocytes expressing the “gut-homing” α4β7 integrin (α4β7 CD8 TL), but may also impact extra-intestinal sites such as the liver in the context of inflammatory bowel disease. To investigate the systemic influence of the local colon tumour immune response, we used a mCRC orthotopic mouse model, in which colon tumour cells are grafted in the colon simultaneously with extra-intestinal locations. In mice, the colon-derived immune response exerted an antimetastatic effect, provoking the elimination of distant, normally progressive, liver or subcutaneous metastases. Immunophenotyping, single-cell RNA and TCR sequencing, as well as cell tracking analyses, uncovered that, once primed by colon tumours, enterotropic tumour-neoantigen specific α4β7 CD8 TL were able to emigrate and infiltrate extra-intestinal tumors. α4β7 CD8 TL then exerted anti-metastatic activities which could be reverted using α4β7 blocking antibodies and could improve the control of liver lesions by anti-PD-L1 immunotherapy. We confirmed the relevance of α4β7 CD8 TL in a cohort of mCRC patients in whom higher expression of α4β7 integrin in metastases and higher numbers of circulating α4β7 CD8 TL were associated with response to immunotherapy. Our findings bring to light the central role of gut-derived α4β7 CD8 TL in systemic cancer immunosurveillance and their potential as biomarkers of responsiveness to immunotherapy in mCRC patients.
Future impact
We uncovered an unexpected “exodus” of enterotropic CD8 TL from the gut toward extra-intestinal tumours, where, in addition, they exhibit superior antitumor abilities as compared to non-intestinal metastases-infiltrating CD8 TL. We will explore which gut-specific components favour the effective priming of antitumor enterotropic α4β7 CD8 TL as well as the mechanisms leading to their gut emigration and extraintestinal trafficking, thus paving the way for new therapeutic strategies aiming to exploit the systemic antitumor activity of intestinal immunity. α4β7 CD8 TL may represent a new predictive biomarker of mCRC response to immunotherapy. For the majority of mCRC patients, who remain unresponsive to current immunotherapies, elicitation of tumour-specific enterotropic α4β7 CD8 TL, through vaccine strategies, involving a “gut-driver”, such as retinoic acid as an adjuvant, could be considered.
Summary of the findings
