PROJET MI-RIOT 1

Ce projet MI-RIOT est porté par l’INSERM et le CIML

CONTEXT & OBJECTIVES

Single-cell transcriptomic landscape reveals tumour- specific innate lymphoid cells associated with colorectal cancer progression.

This project was done in collaboration with Dr Bing Su’s laboratory in Shanghai Institute of Immunology, Shanghai, China.

Innate lymphoid cells (ILCs) are tissue-resident innate antigen- independent lymphocytes that regulate immunity to pathogens and commensal organisms for tissue homeostasis(1). ILCs are classified into five major groups, natural killer (NK) cells, helper-like ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells (1). Given the large amounts and nature of the cytokines they produce, ILC subsets are likely to be involved in cancer immunity but may also contribute to tumor-associated inflammation.

Colorectal cancer (CRC) is the third most prevalent cancer in women and men, and the second most frequent cause of cancer-related deaths worldwide(2), despite remarkable improvements in therapeutic strategies. Dysregulated ILC responses have been linked to the development of intestinal cancers.(3-6)

“Nous sommes particulièrement satisfaits du partenariat avec MSDAVENIR qui permet de lancer des programmes ambitieux d’immunologie fondamentale et d’analyser comment les mécanismes révélés pourraient aussi permettre de proposer des solutions thérapeutiques contre les cancers.“

Eric VIVIER, PU-PH

Directeur du CIML, Coordinateur de Marseille Immunopôle.

Directeur de Recherche à l’Institut de Génétique Humaine, porteur du projet GMarcel BLOT-CHABAUD

RESULTS

We used unsupervised hierarchical clustering to investigate helper-like ILC heterogeneity at steady-state and during CRC in the blood, normal mucosa and gut tumors(7). Compared to normal mucosae, Helper-like ILCs from CRC patients were found to contain two additional subsets: a CRC tissue-specific ILC1-like TIGIT+ subset present in tumors from CRC patients but absent from the blood, and a CRC tissue-specific ILC2 subset, absent from normal mucosae.

The CRC tissue-specific ILC1-like TIGIT+ had a transcriptional profile more closely resembling the ILC1 gene signature than that of any other ILCs. Still, they segregated away from tumor ILC1, suggesting that they differed markedly from ‘conventional’ gut ILC1. Because CRC tissue- specific ILC1-like TIGIT+ cells have high levels of PD1 and TIGIT, they may be further unleashed by anti-PD1 and anti-TIGIT immunotherapies.

Several data support a model in which ILC2s infiltrate tumors via an IL-33-dependent pathway(8-10) and mediate tumor immune surveillance by promoting cytolytic CD8+ T-cell responses. IL-33 is overexpressed in colorectal tumors and high levels of IL-33 are frequently observed in low-grade adenocarcinomas and early colorectal tumors(11). We analyzed that the survival rate is higher in the IL-33-high group of colon cancer patients than in IL-33-low patients, suggesting that CRC tissue- specific ILC2 might be indicative of a good prognosis in CRC. However, PD-1 expression on TILC2 from the late stage of CRC may be of bad prognosis.(12)

PERSPECTIVES

Finally, we identified SLAMF1, a single-chain type I transmembrane receptor, as the only cell surface marker for which transcript levels were higher in ILCs from tumor and blood of CRC patients.

ILCs expressing SLAMF1 on their surface were also present at higher frequency in tumors and blood from CRC patients than in healthy donors. High levels of SLAMF1 were correlated with better survival of CRC patients.

Our results, therefore, suggested that SLAMF1 might be an anti-tumor biomarker in CRC.

PUBLICATIONS

1. E. Vivier et al., Cell 174, 1054-1066 (2018).
2. F. Bray et al., CA Cancer J Clin 68, 394-424 (2018).
3. P. Carrega et al., Gut (2020).
4. A. Fuchs et al., Immunity 38, 769-781 (2013).
5. A. Ikeda et al., Cancer Immunol Res, (2020).
6. Y. Simoni et al., Immunity 46, 148-161 (2017).
7. J. Qi et al., Cell Reports Medicine 2, 100353 (2021).
8. M. F. Chevalier et al., J Clin Invest 127, 2916-2929 (2017). 9. J. A. Moral et al., Nature 579, 130-135 (2020).
10. I. Saranchova et al., Sci Rep 6, 30555 (2016).
11. K. D. Mertz et al., Oncoimmunology 5, e1062966 (2016). 12. S. Wang et al., Cell Res 30, 610-622 (2020).