Melanomas until recently had limited therapeutic options. Immunotherapy, has gained prominence as a therapeutic modality. Despite the high response rate to immunotherapy, it is necessary to decipher biomarkers that predict response to immunotherapy and assess resistance mechanisms towards immunotherapy. To this end, we established a mouse melanoma model to investigate whether tumor mutational burden as well as intratumor heterogeneity affect aggressive tumor cell growth as well as response to immune checkpoint blockade. We identified the antigens that are recognized by tumor infiltrating T cells using HLA peptidomics. This allowed us to identify novel neoantigens, bacteria-derived antigens as well as aberrant peptides derived from translation mistakes, categories of antigens which are further described below.
We focused on the interferon-gamma (IFN‐γ), a cytokine that induces the activity IDO1, which stimulates the production of tryptophan. Along with another amino acid called kynurenine, tryptophan influences the immune response. We know that depletion of tryptophan levels, alongside a parallel accumulation of kynurenine, leads to immunosuppression, but the mechanism leading to the immunosuppression is not fully understood. We used ribosome profiling in melanoma to investigate the effects of IFN‐γ treatment on mRNA translation. We discovered that the depleted levels of tryptophan associated with immunosuppression is associated with frameshifting which occurs during translation that results in the production of multiple unique proteins from a single mRNA. We demonstrated that, after treatment with IFN‐γ, frameshifting led to the generation of aberrant peptides at the cell surface. Our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFN-γ, has a role in the immune recognition of melanoma cells by contributing to diversification of peptides that can be presented and targeted by T cells. We further reported on how bacteria that reside within tumor cells can be harnessed to provoke an immune reaction targeting the tumor. This discovery offers a new avenue for improved cancer immunotherapy and explains the findings of previous research showing that the gut microbiome affects immunotherapy success.
The combination of these discoveries have allowed us to better define the HLA-peptidomic landscape and provide an avenue for personalized treatment using cancer vaccination.
