Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses
Jennifer A. Lo, Masayoshi Kawakubo, Vikram R. Juneja, Mack Y. Su, Tal Hadad Erlich, Martin W. LaFleur, Lajos V. Kemény, Mamunur Rashid, Mohsen Malehmir, S. Alireza Rabi, Rumya Raghavan, Jennifer Allouche, Gyulnara G. Kasumova, Dennie T. Frederick, Kristen E. Pauken, Qing Yu Weng, Marcelo Pereira da Silva, Yu Xu, Anita A. J. van der Sande, Whitney Silkworth, Elisabeth Roider, Edward P. Browne, David Lieb, Belinda Wang, Levi A. Garraway, Catherine J. Wu, Keith T. Flaherty, Constance Brinckerhoff, David W. Mullins, David J. Adams, Nir Hacohen, Mai P. Hoang, Genevieve M. Boland, Gordon J. Freeman, Arlene H. Sharpe, Dieter Manstein, David E. Fisher
Abstract
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.