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No going back (from Kevin Dooley on Flickr).Two papers examine T cells exhausted by chronic exposure to antigen. Sen et al. probed chromatin, finding that exhausted T cells have a signature distinct from other T-cell subsets. Pauken et al. blocked PD-L1, temporarily reinvigorating the exhausted T cells, but when the blockade was lifted, function was lost and the exhausted chromatin signature was retained.Sen DR,…, Haining WN. Science 2016 Oct 27; doi: 10.1126/science.aae0491.Pauken KE,…, Wherry EJ. Science 2016 Oct 27; doi: 10.1126/science.aaf2807.Liver metastases (from Haymanj on WikiCommons).Tumors can express the chemokine receptor CXCR4. The liver produces copious amounts of that receptor's ligand, CXCL12, which can attract and sustain metastases. An engineered CXCL12 trap injected systemically was expressed and secreted locally in the liver, and prevented CXCL12 from binding CXCR4 expressed on tumor cells, thereby reducing liver metastasis.Goodwin TJ,…, Huang L. Sci Transla Med 2016 Nov 7; 364:364ra153; doi: 10.1126/scitranslmed.aag2306.Multivesicular body in cell interior (from Chopra et al. Cancer Res 1981;41:168–75).Lipid movement across endosomal membranes was found to be a means to regulate T-cell activity. Disabling TMEM16F, a scramblase that controls formation of the multivesicular bodies in which TCRs are degraded, enforced a hyperactive state that ultimately resulted in T-cell exhaustion.Hu Y,…, Winau F. J Exp Med 2016 Nov 14;213:2759–72.Intratumoral T cells (from Gabrielson A. Cancer Immunol Res 2016; 4:419–30).Successful immunotherapy requires functional intratumoral T cells. Although a lack of antigen was thought to possibly explain the paucity of T cells in some tumors, when “inflamed” and “noninflamed” melanomas were compared, both contained equivalent amounts of immunogenic antigens. The problem, instead, appeared to reflect, in part, failure to recruit CD141+ Batf3-lineage dendritic cells.Spranger S,…, Gajewski TF. PNAS 2016 Nov 11; doi: 10.1073/pnas.1609376113.Body mimicking wood (from ddouk on Pixabay).Tregs rely on IL2 for their survival and to promote immune suppression. The authors created an antibody (mimobody) that mimics how CD25, an IL2 receptor chain constitutively expressed on Tregs, binds IL2. When delivered to tumor-bearing mice, mimobody-IL2 complexes preferentially expanded tumor-specific CD8 T cells over Tregs, making immunotherapy with mimobody-IL2 complexes more effective than administering IL2.Arenas-Ramirez N,…, Boyman O. Sci Transla Med 2016 Nov 30; 8:367ra166.Good combinations (from PEXELS).Tumors can rarely be controlled with a single approach. By combining four different immunotherapies (a powerful vaccine, long-lived IL2, tumor antigen–targeting antibodies, and anti–PD-1), large tumors of different lineages regressed in multiple mouse models.Moynihan KD,…, Irvine DJ. Nat Med 2016 Oct 24; doi: 10.1038/nm.4200.