Research ArticleCancer

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses

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Science Translational Medicine  17 Feb 2021:
Vol. 13, Issue 581, eabd8636
DOI: 10.1126/scitranslmed.abd8636

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Spreading the immune response to melanoma

Immune checkpoint inhibitors (ICIs) have revolutionized treatment for patients with melanoma, although not all patients respond. Here, Lo et al. showed that patients with the best responses to ICI often develop immune responses to melanocyte-lineage epitopes. The authors then showed that inducing mutations in murine melanomas in combination with ICI resulted in T cell responses to the induced mutations plus inflammation that provoked epitope spreading to the targeting of healthy melanocyte antigens. The response to melanocyte antigens led to better long-term control of melanomas and rejection of secondary melanoma challenges a finding that was mimicked by alternatively inducing inflammation with localized laser and imiquimod treatment. Thus, combining methods to induce localized inflammation plus ICI may represent a therapeutic option for patients with suboptimal responses to ICI alone.

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.

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