A Sampling of Highlights from the Literature

Abstract

Assistance from NK cells yields effective kinase inhibitor therapy (by N. Youngson via Picpedia.org)Chemotherapy that is targeted to tumor cells can also induce antitumor effects through other cells. Ruscetti et al. examined MAP kinase and CDK 4/6 inhibitors and found that only when used together can they suppress proliferation of KRAS-mutated lung cancer cells and promote an NK-cell program that is required for tumor cell death. This process is mediated through RB (a tumor suppressor)-induced cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components include TNFα and ICAM-1, which are required for NK-cell tumor surveillance, killing, and tumor control.Ruscetti M, …, Lowe SW. Science 2018 Dec; 362:1416–22.FLIPping NF-kB to the nucleus (from Fig. 5 of A. Fiore, Nat Comm 2018)Eliminating monocytic myeloid-derived suppressor cells (M-MDSCs) reduces immunosuppression. Fiore et al. find that c-FLIP in myeloid cells has dual roles. Drugs that downregulate FLIP selectively eliminate M-MDSCs, but not polymorphonuclear (PMN)-MDSCs, and decrease chemotherapy resistance. FLIP expression, however, also directly influences M-MDSC immunosuppression by activating immunosuppressive pathways, increasing NF-κB nuclear translocation, and activating inflammatory networks. Pancreatic ductal carcinomas express elevated numbers of c-FLIP+ monocytes, and high percentages of c-FLIP+ PD-L1+CD14+ cells correlate with shorter overall survival. Manipulation of FLIP in monocytes may curtail cancer-associated inflammation and immune dysfunction.Fiore A, …, Bronte V. Nat Commun 2018 Dec; 9:5193–205.ADAR1′s active site (by Devon286 via Wikimedia Commons)Not all patients exhibit objective responses to immune checkpoint blockade due to both tumor cell extrinsic and intrinsic mechanisms. Ishizuka and colleagues demonstrate the key role of tumor ADAR1, an RNA-editing enzyme, in responses to immunotherapy. Deletion of ADAR1 alters editing of interferon-inducible transcripts, resulting in tumor growth inhibition, increased T-cell and NK-cell infiltration, reversal of tumor-mediated inhibition of antigen presentation, and sensitization of the tumors to interferons and anti–PD-1 therapy. Thus, targeting ADAR1 could boost responses in patients receiving immunotherapies.Ishizuka JJ, …, Haining WN. Nature 2018 Dec; 565:43–48.Glioblastoma (by Sbrandner via Wikimedia Commons)A personalized neoantigen-based vaccine was tested in patients with glioblastoma. Tumor and normal tissue were compared by whole-exome sequencing, to identify genetic variants. Eight of ten patients had sufficient neoepitopes from which to generate vaccines consisting of about 12 neopeptides with an average length of 24 amino acids. The dexamethasone often given to these patients negatively correlates with antigen-specific T-cell responses, which are associated with better infiltration of the glioblastoma. T cells in the tumor express multiple inhibitory receptors, suggesting that pairing this vaccination with checkpoint blockade would be a rational approach to the treatment of glioblastoma.Keskin DB, …, Reardon DA. Nature 2018 Dec; 565:234–9.Dual blockade enhances offense (2nd Lt. J. Ross via U.S. Air Force)The mechanisms behind responses to immunotherapies are not completely elucidated. André et al. identify the NKG2A receptor as an inhibitory checkpoint molecule and develop a humanized anti-NKG2A IgG4 blocking antibody, monalizumab. NKG2A blockade augmented NK- and T-cell responses and enhanced the efficacy of immune checkpoint blockade and anti-EGFR treatment in mice and humans, demonstrating the potential to target NKG2A in combination with other immunotherapies.André P, …, Vivier E. Cell 2018 Dec 13; 175:1731–43.e13.Class-based paths to resistance (by USDA via Wikimedia Commons)Tumors can acquire resistance to checkpoint blockade. MHC-II expression is a predictor of anti–PD-1 response, and Johnson et al. show, in tumor samples from patients treated with anti–PD-1, that MHC-II+ tumors facilitate CD4+ T-cell infiltration and antitumor immunity. As the cancer progresses and/or during immune checkpoint blockade, MHCII+ tumors acquire resistance to therapy due to increased expression of Lag-3 and increased Fc receptor–like 6 (FCRL6) in the tumor microenvironment, which provide inhibitory signals to immune cells. This immune pattern found in MHCII+ tumors suggests an MHC-mediated mechanism behind immunotherapy resistance.Johnson DB, …, Balko JM. JCI Insight 2018 Dec 20; 3:e120360.