Abstract:

Targeting the immune checkpoint PD-1 has revolutionized the treatment of metastatic melanoma. Nevertheless, 60% of patients are resistant to this immunotherapy highlighting the urgency to develop new therapeutic strategies. The microbiota is determinant for the correct development and function of the immune system. Consequently, alterations in its composition impact health and promote the development of disease. In cancer, perturbations of the microbiota have been shown to impair anti-tumoral immunity and the response to anti-PD1 immune checkpoint blockade. Amino acid catabolic enzymes are overexpressed in many tumors where they have been associated to a poor prognosis, mainly attributed to their immunosuppressive properties.  My team has demonstrated the implication of the L-amino acid oxidase IL-4-induced gene 1 (IL4I1) in tumor escape using mice transgenic for the RET human oncogene developing a spontaneous uveal metastatic melanoma. Indeed, the genetic inactivation of the enzyme delays tumor while promoting tumor microenvironment remodeling. Considering that IL4I1 also possesses a bactericidal activity highly conserved phylogenetically we hypothesized that IL4I1 may alter the microbiota contributing to tumor aggressiveness.

Here, using different housing conditions we demonstrated that IL4I1 promotes tumor development via an impact on microbiota in the RET spontaneous melanoma model. Particularly, cross-fostering experiments revealed the presence of pro-tumoral bacteria in RET mice

and anti-tumoral bacteria in RET-IL4I1KO mice. 16S rRNA gene sequencing of feces, eyes and skin (tumor sites) from RET and RET-IL4I1KO mice uncovered an IL4I1-mediated dysbiosis in all 3 compartments of RET mice. Taxonomical analysis enabled the identification of an enrichment of Jeotgalicoccus psychrophilus and Staphylococcus in RET mice, being potentially antitumoral bacteria. Increased abundance of Parabacteroides distasonis (PD) and Mediterraneibacter gnavus (MG) in RET-IL4I1KO mice suggested a potentially anti-tumoral role of these bacteria. Interestingly, skin microbiota modulation with PD or MG elicited a better tumor control compared to oral administration in RET transplanted melanoma. This enhanced protection was associated to changes in the number and function of infiltrating T cells towards an anti-tumoral profile. Interestingly, treatment of RET mice bearing measurable cutaneous metastases revealed that topical application with PD or MG not only impaired cutaneous metastases growth but also conferred a long distant protection, as demonstrated by the reduction of bladder and lung metastases. Topical application of either bacterium also improved PD1 blockade efficacy.

Overall, our results demonstrate that IL4I1 promotes tumor development by altering microbiota and that modulating the skin microbiota can restore anti-tumoral responses paving the way for the development of new therapeutic strategies targeting the cutaneous microbiota to enhance cancer immunotherapy.