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Abstract

MMR hypermutations (from Mouradov, Cancer Res 2014;74:3238)More than 80,000 adult and childhood tumors were examined for mutation frequencies across tumor types and the contribution of intrinsic and extrinsic mutators. The data allowed the prediction of past mutagen exposure and the identification of new drivers of hypermutator phenotypes, including prior chemotherapy. The order of mutational signatures leading to hypermutation was deduced, providing potential insights into tumor classification, patient management, and genetic testing.Campbell BB, …, Shlien A. Cell 2017 Nov 16;171:1042–1056.e10.Intestinal flora (from Bonnet, Clin Can Res 2014;20:859)Two clinical studies confirm mouse models that suggested that responses to anti–PD-1 therapy in patients with melanoma (Gopalakrishnan et al.) or kidney, lung, or bladder tumors (Routy et al.) correlate with gut microbiome composition. Antibiotics before or during therapy hastened relapse and shortened survival. Germ-free or antibiotic-treated mice transplanted with patient feces from responders had enhanced therapeutic responses to PD-1 blockade. Specific bacterial types comprised favorable microbiomes, so manipulating microbiota may provide another therapeutic approach to enhance cancer treatment.Routy B, …, Zitvogel L. Science 2017 Nov 2; DOI: 10.1126/science.aan3706.Gopalakrishnan V, …, Wargo JA. Science 2017 Nov 2; DOI: 10.1126/science.aan4236.Pancreatic tumor (from Shakya, Cancer Res 2012;73:885)Few patients with pancreatic cancer become long-term survivors. Potential T-cell responses that could be beneficial in long-term survivors were examined in depth. Tumors with high neoantigen loads and abundant CD8+ T-cell infiltrates were associated with the longest survival. Neoantigen quality, as defined by similarities to microbial peptides or with MUC16 neoepitopes, improved survival predictions. T cells to these antigens could be detected in tumors and in long-term survivors. The high-quality neoantigens were often lost upon metastatic progression, perhaps reflecting immune editing.Balachandran VP, …, Leach SD. Nature 2017 Nov 8. DOI: 10.1038/nature24462.Fatty liver (from Nephron via Wikimedia Commons)Patients with fatty-liver disease have more circulating IgA and a propensity to develop hepatocellular carcinoma (HCC). The IgA is likely produced by plasmocytes that can develop by TGFβ-mediated conversion from IgM- to IgA-expressing B cells, and which accumulate in the fibrotic liver. In animal models of nonalcoholic steatohepatitis, these IgA-producers express PD-L1 and suppress antitumor activity of CD8+ CTLs. Depletion of T cells accelerates the development of HCC, whereas ablation of IgA-producing cells reduces tumor development. Blockade of PD-L1 induces tumor regression presumably by targeting PD-L1+ plasmocytes, as the benefit was lost in mice lacking IgA+ cells.Shalapour S, …, Karin M. Nature 2017 Nov 8;551:340–5.CAFs in suppressive tumor environment (from Granot & Fridlender, Cancer Res 2015;75:4441)An unintended consequence of CSF1R blockade (which depletes tumor-associated macrophages) was an increase in myeloid-derived suppressor cells (PMN-MDSCs), thwarting any antitumor effects. CSF1 produced by tumor cells downregulated granulocyte-specific chemokine expression in cancer-associated fibroblasts, and treatment with CSF1R inhibitors disrupted this crosstalk, triggering increased recruitment of PMN-MDSCs. In a mouse tumor model, combining CSF1-R blockade with a CXCR2 antagonist blocked PMN-MDSC infiltration, resulting in potent antitumor effects.Kumar V, …, Gabrilovich DI. Cancer Cell 2017 Nov 13;32:654–68.e5.Transferring mobile information (by Tableatny via Flickr)Macrophages are often associated with tumor progression. In a human-in-zebrafish xenograft model of melanoma, M2 macrophages were recruited in a MyD88-dependent fashion and stayed in prolonged contact with tumor cells. Macrophages transferred cytoplasm to the tumor cells, which correlated with tumor cell dissemination. Cytoplasmic material presumably can be transferred from macrophages by multiple mechanisms, although the nature of the critical pathway(s) and active moieties being transferred are as yet unknown.Roh-Johnson M, …, Moens CB. Dev Cell 2017 Dec 4;43:549–62.e6.56yu7t.