[Research Articles] Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses

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...

Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Lo, J. A., Kawakubo, M., Juneja, V. R., Su, M. Y., Erlich, T. H., LaFleur, M. W., Kemeny, L. V., Rashid, M., Malehmir, M., Rabi, S. A., Raghavan, R., Allouche, J., Kasumova, G., Frederick, D. T., Pauken, K. E., Weng, Q. Y., Pereira da Silva, M., Xu, Y., v Tags: Research Articles Source Type: research