Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses
| Autor: | Dieter Manstein, Martin W. LaFleur, Arlene H. Sharpe, Marcelo Pereira da Silva, Lajos Kemény, Mack Y. Su, Kristen E. Pauken, Masayoshi Kawakubo, David E. Fisher, S. Alireza Rabi, Tal Hadad Erlich, Catherine J. Wu, Rumya Raghavan, Genevieve M. Boland, Edward P. Browne, Mamunur Rashid, Yu Xu, Mai P. Hoang, Dennie T. Frederick, Jennifer A. Lo, Constance E. Brinckerhoff, Jennifer Allouche, David W. Mullins, David J. Adams, Anita A. J. van der Sande, Vikram R. Juneja, Mohsen Malehmir, Levi A. Garraway, David J. Lieb, Gordon J. Freeman, Keith T. Flaherty, Gyulnara G. Kasumova, Belinda Wang, Elisabeth Roider, Nir Hacohen, Whitney Silkworth, Qing Yu Weng |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 (PD-1), can deliver durable anti-tumor 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 ICIs 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 ICIs can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, skewing 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 anti-tumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope skewing toward T cell recognition of wild type tumor-lineage self-antigens represents a common pathway for successful response to ICIs, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod. |
| Databáze: | OpenAIRE |
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