No abstract

Although immune checkpoint inhibitors (ICIs), such as anti–programmed cell death protein–1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti–PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti–PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti–PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.

Microphthalmia transcription factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) DNA-binding protein. This transcription factor plays a crucial role in the physiological and pathological functions of distinct cell types. MITF transcriptional activity is inhibited by the histidine triad nucleotide-binding protein 1 (HINT1) through direct binding. We previously reported that this association is disrupted by the binding of the second messenger ApA to HINT1. ApA is mainly produced in the mammalian cells by S207-phosphorylated Lysyl-tRNA synthetase. In this study, we found first that HINT1 was subjected to K21 acetylation and Y109 phosphorylation in activated mast cells, together with the ApA-triggered HINT1 dissociation from MITF. Mutational analysis confirmed that these modifications promote MITF transcriptional and oncogenic activity in melanoma cell lines, derived from human melanoma patients. Thus, we provided here an example that manipulation of the LysRS-ApA-HINT1-MITF signalling pathway in melanoma through post-translational modifications of HINT1 can affect the activity of the melanoma oncogene MITF.

The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.