Highlights of This Issue

Abstract

MAIT cells are most enriched in the liver, comprising up to 50% of all intrahepatic T cells. Duan and colleagues aimed at determining the distribution, phenotype, function, and clinical relevance of MAIT cells in human HCC. They found that HCC-infiltrating MAIT cells' cytotoxic capability was significantly impaired with upregulation of PD-1, CTLA-4 and TIM-3. Still worse, infiltrating MAIT cells were reprogramed to a tumor-promoting direction as exemplified by RNA-seq, cytokine secretion profile and in vitro coculture assay, and correlated with dismal clinical outcomes. This study shows promise for modulating MAIT cells' function in antitumor therapy in HCC.Overcoming tumor-related immunosuppression presents a significant obstacle to successful cancer treatment. To activate the host's antitumor immunity, Viitala and colleagues exploited macrophage reprogramming as an alternative approach to stimulate CD8+ T-cell–mediated tumor cell killing. Genetic deficiency or immunotherapeutic targeting of macrophage Clever-1 induced IL-12 secretion and MHCII expression by tumor-associated macrophages, and markedly impaired solid tumor growth in multiple syngeneic mouse tumor models. Notably, the effects were similar to those achieved by PD-1 checkpoint inhibition, and thus support the clinical evaluation of Clever-1 blockade as a novel cancer treatment strategy.NOTCH1 loss-of-function mutations are common in head and neck squamous cell carcinoma (HNSCC). Sambandam and colleagues demonstrate that NOTCH1-mutant HNSCC undergoes cell death when exposed to PI3K inhibitors, which was linked to drug-induced suppression of PDK1. In contrast, PIK3CA mutant cell lines merely undergo cell cycle arrest when exposed to the same drugs. This is the first study to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC to any class of drugs and may inform the development of the first biomarker-driven therapy for HNSCC. This research led to the initiation of a clinical trial testing a PI3K/mTOR inhibitor in NOTCH1 mutant HNSCC (NCT03740100).Chemokine receptor CXCR2 drives immune escape and chemoresistance in human cancers. To explore its role in gastric cancer (GC) metastasis, Zhou and colleagues established the lymph node metastasis model and a coculture system of GC cells and macrophages to demonstrate that macrophages promote migration of GC by activating a CXCR2/STAT3 feed-forward loop in a CXCL1/CXCL5-dependent manner, and GC cells increase the expression of CXCL1/CXCL5 in macrophages by secreting TNF-α. This study identified a CXCR2 dominated cross-talk between GC cells and macrophages, and thus provides a potential therapeutic target for GC treatment.