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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.

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

Becoming-animal in Franz Kafka has functioned as a conceptual inkblot test, read in practically opposite ways by Gilles Deleuze and Félix Guattari on the one hand and animal studies on the other. The concept is introduced in Kafka: Towards a Minor Literature , a text with no particular interest in displacing anthropocentrism. On the contrary, Deleuze and Guattari saw Kafka as an affirmatively anthropocentric writer who needed to have done with animals in order complete his anti-fascist accelerationist project. Yet ecocritical readers of Deleuze and Guattari have nevertheless found in becoming-animal a weapon against anthropocentrism. While Deleuze and Guattari attempt to purify Kafka of animality, animal studies for its part purifies both Kafka and Kafka of anti-fascism. The roots of this strange conceptual chiasmus lie in the manner in which the opposition nature-techne is thought and a certain shared Heidegerrian inheritance. A reading of Kafka's The Castle focusing on a horse-drawn sleigh provides resources for a concept of animal machine that would ruin the opposition between becoming-animal and machinic assemblage (nature-techne) that governs Kafka and blocks access to crucial resources for countering fascism and anthropocentrism. [ABSTRACT FROM AUTHOR]

We report experimental studies to understand the reaction mechanism of the intermetallic anode Cu2Sb with Na and demonstrate that it is capable of retaining about 250 mAh g-1 over 200 cycles when using fluoroethylene carbonate additive. X-ray diffraction data indicate during the first discharge the reaction leads to the formation of crystalline Na 3Sb via an intermediate amorphous phase. Upon desodiation the Na 3Sb reverts to an amorphous phase, which then recrystallizes into Cu2Sb at full charge, indicating a high degree of structural reversibility. The structure after charging to 1 V is different from that of Cu2Sb, as indicated by X-ray absorption spectroscopy and 121Sb Mössbauer spectroscopy, and is due to the formation of an amorphous Na-Cu-Sb phase. At full discharge, an isomer shift of -8.10 mm s -1 is measured, which is close to that of a Na3Sb reference powder (-7.95 mm s-1) and in agreement with the formation of Na3Sb domains. During charge, the isomer shift at 1 V (-9.29 mm s-1) is closer to that of the pristine material (-9.67 mm s -1), but the lower value is consistent with the lack of full desodiation, as expected from the potential profile and the XAS data. © 2014 American Chemical Society.