Fusobacterium nucleatum as surrogate target for colorectal cancer immunotherapy

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Current treatments, including immunotherapies based on immunological checkpoint blockade (ICB), are largely ineffective as CRC is most frequently characterized by low mutational load and related paucity of neoantigens.

Defined bacteria of gut microbiota are enriched in CRC and may favor tumor growth. In particular, Fusobacterium nucleatum (Fn), is detected in primary and metastatic CRCs and its abundance correlates with unresponsiveness to treatments and unfavorable prognosis. Fn has been shown to invade CRC cells and mediate pro-tumorigenic effects, by enhancing cancer cell proliferation and promoting drug resistance.

Notably, proteomic analysis has identified Fn-derived epitopes associated with HLA molecules at tumor cell surface. These findings suggest that Fn might provide “surrogate” tumor antigens which may be recognized by specific T cells.

We have recently observed that in peripheral blood mononuclear cells of healthy donors and patients with CRC, Fn induces expansion of CD8+ ad CD4+ T cells endowed with cytotoxic properties.

Based on this background, we hypothesize that T cell-mediated immune responses specific for Fn might target infected CRC cells in primary and metastatic lesions, with effective anti-tumor potential.

Therefore, in this proposal we intend to address the following specific aims:

1) Assessment of the ability of Fn-specific T cells from healthy donors and patients with CRC to kill Fn-infected CRC cells in vitro.

2) Evaluation of the ability of Fn-specific T cells to mediate anti-tumor effects in vivo, in orthotopic CRC xenograft mouse models, in the presence or absence of immunological checkpoint blockade.

A successful implementation of this project will verify the ability of Fn-specific T cells to effectively kill infected tumor cells and might provide the rationale for the development of innovative adoptive immunotherapies, aimed at overcoming the paucity of neo-antigens in CRC cells through targeting of CRC-associated bacteria of unfavorable prognostic significance.