A Sampling of Highlights from the Literature.

Abstract

Lactic acid is a metabolic checkpoint for Treg cells (from Jynto via Wikimedia Commons)The intratumoral ratio of CD8+ T cells to regulatory T (Treg) cells impacts responsiveness to PD-1 blockade. Kumagai et al. find the ratio of CD8+ T cells to Treg cells is low in highly glycolytic tumors, including MYC-amplified tumors and liver metastases, and that expression of PD-1 is lower in CD8+ T cells than Treg cells. This effect is mediated by tumor-derived lactic acid and leads to resistance to PD-1 blockade in mouse models of Myc-overexpressing colon cancer and intrahepatic tumors. Blocking lactic-acid production or its uptake by Treg cells overcomes this resistance, suggesting potential new targets for cancer immunotherapy.Kumagai S, …, Nishikawa H.Cancer Cell2022 Feb 14;40:201–18.e9.Pancreatic cancer can be protected from CAR T cells by N-glycans (from Neelima Shah and Edna Cukierman via NCI Visuals Online)Chimeric antigen receptor (CAR) T-cell therapy has limited efficacy against solid tumors. Greco et al. identify expression of N-linked glycans as a targetable barrier to killing of solid tumors by CAR T cells. Knockout of mannoside acetyl-glucosaminyltransferase 5 and exposure to 2-deoxy-D-glucose (2DG), both of which disrupt N-glycan expression, render T3M-4 human pancreatic cancer cells sensitive to killing by CD44v6-targeted CAR T cells in vitro. Treatment with 2DG enhances tumor-cell killing by CAR T cells in xenograft models of pancreatic, ovarian, bladder, and lung cancer, suggesting a new approach to improve CAR T-cell therapy for solid tumors.Greco B, …, Casucci M.Sci Transl Med2022 Jan 19;14:eabg3072.Blocking “don’t eat me” signals increases macrophage phagocytosis (from QuidsUp)Modulation of macrophage phagocytosis is a tumor escape mechanism. Li et al. find a role for signaling lymphocytic activation molecule (SLAM) family receptors (SFR) in limiting macrophage phagocytosis by hematopoietic tumors. Specifically, SLAMF3 and SLAMF4 are identified as “don’t eat me” receptors on macrophages. Deficiency in SFRs, with and without CD47 deficiency, increases phagocytosis of hematopoietic cells (i.e., “self”) and malignant cells, highlighting a novel signaling pathway that can modulate the function of macrophages in the tumor microenvironment.Li D, …, Dong Z.Sci Immunol2022 Jan 21;7:eabj5501.HLA-A*03 is associated with poor response to immune checkpoint blockade (from Pdeitiker via Wikimedia Commons)Human leukocyte antigens (HLA) play a vital role in immunity, and thus, could impact immunotherapy efficacy. Using multiple large-scale datasets, Naranbhai et al. identify HLA-A*03 as a biomarker of response to immunotherapy but not response to other types of cancer treatment. Expression of this HLA associates with worse progression-free survival and lower responses to immune checkpoint inhibitors, which was validated in several independent cohorts of patients with various tumor types.Naranbhai V, …, Carrington M. Lancet Oncol 2022 Jan 1;23:172–84.Understanding of the NSCLC immune landscape continues to deepen (from Librepath via Wikimedia Commons)Deepening understanding of the immune landscape of non–small cell lung cancer (NSCLC) can help identify biomarkers of response to immunotherapy. Using single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), Leader et al. find a strong correlation between PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages; they refer to these cells collectively as the lung cancer activation module (LCAM). The LCAMhi phenotype correlates with tumor mutational burden, TP53 mutations, and response to anti–PD-L1 therapy but not chemotherapy, suggesting that it could be a new biomarker of NSCLC response to immunotherapy.Leader AM, …, Merad M. Cancer Cell 2021 Dec 13;39:1594–609.e12.TRIB3 regulates CD8+ T-cell exclusion in the tumor microenvironment (from Max Pixel)Colorectal cancer resistance to immune checkpoint therapy is partly attributable to a lack of tumor-infiltrating T cells. Shang et al. report that TRIB3 expression in tumor cells correlates with CD8+ T-cell exclusion in mouse models of colorectal cancer and human samples. TRIB3 expression inhibits expression of the T cell–recruiting chemokine CXCL10 by activating STAT3, which inhibits transcription of STAT1 and subsequently CXCL10. Inhibition of the P300 acetylase, which acetylates TRIB3 and prevents E3 ligase–mediated degradation, improves CD8+ T-cell infiltration and sensitizes colorectal tumors to checkpoint blockade in vivo, suggesting a therapeutic strategy to improve immunotherapy efficacy in immunologically “cold” colorectal tumors.Shang S, …, Hua F. Sci Transl Med 2022 Jan 5;14:eabf0992.