Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 Somatic Single Nucleotide Variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the NOTCH pathway (NOTCH1 and NOTCH2). Virus-negative MCCs harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P¼0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virusnegative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

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Generalized pustular psoriasis (GPP) is a rare, recurrent, and life-threatening disease, characterized by the infiltration of neutrophils into the epidermis to form generalized pustules. Neutrophils are the most abundant leukocytes present in human blood and in the lesional skin of GPP patients. Though short-lived, neutrophils can immediately secrete cytokines, chemokines, and vesicles. Our study aimed to illustrate the functions of neutrophils in the immune disorder of GPP. Herein, we demonstrated that the neutrophil to lymphocyte ratio (NLR) was correlated with the severity of GPP, and decreased dramatically after effective treatment, which indicated that the NLR score could be a marker for the severity and prognosis of GPP, and neutrophil might play a critical role in the pathogenesis of GPP. Besides, keratinocytes co-cultured with GPP neutrophils indirectly produced more CXCL1, CXCL2, CXCL8, CCL20, IL36G, and TNF-a than those in the direct co-culturing system. Further, exosomes derived from GPP neutrophils could enter and activate keratinocytes to secrete the above-mentioned mediators. The proteome profiling of GPP neutrophil exosomes identified olfactomedin 4 (OLFM4) as a critical distinct protein. And neutrophil exosomes with OLFM4 cargo activated keratinocytes to highly produce these chemokines and cytokines via NOD2 and the downstream NF-kb and MAPK signaling pathways. Importantly, the proportion of OLFM4-positive neutrophils was found to be higher in patients with progressive GPP than that in controls. Taken together, these data suggest that neutrophil-derived exosomes enter keratinocytes to stimulate the expression and secretion of CXCLs, IL36G, and TNF-a, resulting in the chemotaxis of more neutrophils, which promotes the autoinflammatory responses in generalized pustular psoriasis.

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