Highlights of This Issue

Abstract

Many cancer patients do not respond to immunotherapy, and new strategies are needed to overcome resistance. To explore molecular mechanisms of resistance to immunotherapy, Huang and colleagues performed a screen using patient-derived melanoma cells and autologous TILs, and they identified the RNA-binding protein MEX3B as a novel target associated with immunoresistance. MEX3B binds to HLA-A 3′ UTR and destabilizes HLA-A mRNA, thus downregulating HLA-A expression and blocking tumor recognition by T cells. These findings may lead to the development of therapeutic strategies targeting MEX3B, in the hope of overcoming immunoresistance and achieving better clinical outcomes for melanoma patients treated with immunotherapy.PD1 receptor is a known negative regulator of T lymphocytes. Sanlorenzo and colleagues explored the biological relevance of PD1 directly expressed by melanoma cells, where it can promote tumor growth. Under baseline conditions, PD1 was consistently expressed by melanoma at very low levels, and its blockade did not have a relevant effect on tumor growth; however, upon treatment with BRAF and MEK inhibitors (BRAF/MEKi), the rates of PD1+ melanoma cells significantly increased. In a preclinical immunodeficient model, the blockade of PD1 on melanoma cells prolonged the response to BRAF/MEKi and delayed tumor relapse, supporting the basis for a lymphocyte independent synergism.Through analyzing the copy number profiles of 10,759 tumor genomes of 31 cancer types, Ye and colleagues found the type-I interferon, α- and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies. Deletion of interferon and defensin genes activated oncogenic and cell cycle pathways while repressed immune response pathways. Importantly, these homozygous deletions associated with shortened overall or disease-free survival in a number of cancer types and the anti-CTLA-4 immunotherapy resistance in metastatic melanoma patients. This study reveals the deletion of interferon/defensin as potential prognostic and predictive biomarker for immunotherapy resistance.Claret and colleagues explored model-based estimates of on-treatment growth rate constant to predict overall survival (OS) benefit (hazard ratio) with atezolizumab versus docetaxel in NSCLC. A multivariate OS model was developed based on phase II POPLAR study and externally validated in predicting phase III study OAK OS HR (in all comers as well as by PD-L1 expression) based on early tumor kinetic data (40 weeks) before OS maturation. In both studies, PFS was similar between arms. On-treatment growth rate constant is proposed as an early endpoint to support decisions in cancer immunotherapy studies.