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INKT CELL-NEUTROPHIL CROSSTALK PROMOTES COLORECTAL CANCER PATHOGENESIS

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Introduction

iNKT cells account for a relevant fraction of effector T-cells in the intestine and are considered an attractive platform for cancer immunotherapy. Moreover, human iNKT cells possess cytotoxic properties through the perforin–granzyme pathway [1]. However, their role in CRC progression has never been fully elucidated and it is still controversial. Reduced frequencies and functional impairment of iNKT cells associated with loss of IFNγ secretion have been associated with poor overall survival in solid or hematological tumors. Nevertheless, αGalCer administration can revert iNKT cells functional impairment as demonstrated in preclinical studies and clinical trials. Additionally, the gut microbiota is an oncogenic driver of CRC and intestinal microbes represent potent stimulators of iNKT cell responses that can shape their functions.

Aims & Methods

In this study we aim to address the contribution of iNKT cells to CRC pathophysiology and the effect of the tumor-associated microbiota in shaping their pro- or anti- tumorigenic functions.
To gain insights into iNKT cells role in CRC we examined the immune cell composition and iNKT cell phenotype of paired non-tumor vs cancerous tissue lesions in CRC patients (n=118) diagnosed at the Policlinico Hospital, Milan, Italy, between January 2017 and July 2022.
High-dimensional single-cell flow cytometry, metagenomics and RNAseq experiments and ex vivo and in vitro experiments were performed to evaluate the phenotype and function of human iNKT cells. Mechanisms were dissected in chemically-induced or orthotopically implanted (subcutaneous or intracaecal) CRC murine models, either iNKT proficient or deficient. RFS analyses were performed in our cohort of patients and results were validated in the colon adenocarcinoma cohort (COAD) of The Cancer Genome Atlas (TCGA) database.

Results

The immunophenotypic profiles of ex vivo isolated human iNKT cells and the use of different iNKT cell-deficient murine strains confirmed that IFNγ-producing, cytotoxic iNKT cells limit colonic tumorigenesis whereas intratumor accumulation of GM-CSF+IL17+iNKT cells support colon cancer progression.
Human iNKT cell stimulation with F. nucleatum, enriched in our cohort, promotes their commitment towards a protumor GM-CSF+IL17+ phenotype. Moreover, F. nucleatum induced a neutrophil chemotaxis gene signature in iNKT cells. Neutrophils exposed to F. nucleatum-primed iNKT cells manifested a PMN-MDSCs gene signature and immune suppressive activity as demonstrated by in vitro functional assays. Lack of iNKT cells in tumor-bearing mice mice reduced tumor burden and recruitment of immune suppressive neutrophils. The beneficial role of neutrophils in CRC is dependent on iNKT cells, since concomitant high infiltration of iNKT cells is a negative prognostic factor in our patients’ cohort and in the TCGA-COAD database. Importantly, iNKT cells in vivo reactivation with αGalCer restored their anti-tumor function suggesting that iNKT cells can be modulated to overcome CRC-associated immune evasion.

Conclusion

Our results reveal a functional plasticity of iNKT cells in CRC, showing that tumor-infiltrating iNKT cells can contribute to the remodeling of the TME by recruiting TANs in the early phases of tumor progression, thereby sculpting the CRC developmental trajectory. Our findings uncover cellular and molecular mechanisms through which the iNKT-TAN axis can suppress antitumor immunity in CRC, supporting the targeted manipulation of iNKT cells’ function to improve cancer immunotherapies and adoptive cell therapies based on CAR/TCR-engineered iNKT cells.

References

1. Diaz-Basabe, A., et al., Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin-granzyme pathway. Mol Oncol, 2021. 15(12): p. 3385-3403