Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Lo Jennifer A,Kawakubo Masayoshi,Juneja Vikram R,Su Mack Y,Erlich Tal H,LaFleur Martin W,Kemeny Lajos V,Rashid Mamunur,Malehmir Mohsen,Rabi S Alireza,Raghavan Rumya,Allouche Jennifer,Kasumova Gyulnara,Frederick Dennie T,Pauken Kristen E,Weng Qing Yu,Pereira da Silva Marcelo,Xu Yu,van der Sande Anita A J,Silkworth Whitney,Roider Elisabeth,Browne Edward P,Lieb David J,Wang Belinda,Garraway Levi A,Wu Catherine J,Flaherty Keith T,Brinckerhoff Constance E,Mullins David W,Adams David J,Hacohen Nir,Hoang Mai P,Boland Genevieve M,Freeman Gordon J,Sharpe Arlene H,Manstein Dieter,Fisher David E Science translational medicine 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. 10.1126/scitranslmed.abd8636

Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Richmond Jillian M,Strassner James P,Zapata Lucio,Garg Madhuri,Riding Rebecca L,Refat Maggi A,Fan Xueli,Azzolino Vincent,Tovar-Garza Andrea,Tsurushita Naoya,Pandya Amit G,Tso J Yun,Harris John E Science translational medicine Vitiligo is an autoimmune disease of the skin mediated by CD8 T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (T) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired T formation, and IL-15 promotes T function ex vivo. We found that both human and mouse T express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits T production of interferon-γ (IFNγ), and long-term treatment depletes T from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving T. 10.1126/scitranslmed.aam7710

Resident memory CD8 T cells in regional lymph nodes mediate immunity to metastatic melanoma. Immunity The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8 T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer. 10.1016/j.immuni.2021.08.019