A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.

Abstract

A two-step circuit allows ultrasensitive sensing of antigen density (from Ron Mader via Flickr)Recognition of normal cells expressing a low density of target antigen is a barrier to chimeric antigen receptor (CAR) T–cell therapy for some cancers. Hernandez-Lopez et al. have designed a two-step antigen-recognition circuit enabling CAR T cells to distinguish cells expressing high and low densities of target antigen. They engineer T cells to express a synthetic Notch receptor with low affinity for HER2. HER2 recognition by this receptor drives expression of a CAR with high affinity for HER2. These cells kill tumor cell lines and 3D spheroids expressing high densities of HER2 but spare those with low densities of HER2, showing this approach could limit on-target, off-tumor responses.Hernandez-Lopez RA, …, Lim WA. Science 2021 Mar 12;371:1166–71.Alveolar rhabdomyosarcoma (from Nephron via Wikimedia Commons)Increased understanding of the microenvironment at distant sites prior to metastases becoming detectable at those sites could lead to new strategies for treating metastases. In a syngeneic orthotopic model of rhabdomyosarcoma that spontaneously metastasizes to the lungs, Kaczanowska et al. identify a transcriptional program indicative of myeloid-mediated immune suppression in the premetastatic lung. Intravenous administration of myeloid cells genetically engineered to express IL12 reprograms the premetastatic niche, reversing the immunosuppressive phenotype and inducing T cell–mediated antitumor immunity, such that metastases are reduced and survival improved. These data suggest a new strategy for treating metastatic disease.Kaczanowska S,…, Kaplan RN. Cell 2021 Apr 15;184:2033–52.e21.MRTFs play dual roles in cancer and antitumor immunity (from Fig. 1 of Finch-Edmondson et al., Cell Mol Biol Lett 2016)Tumor cells have multiple ways of evading immune detection. Tello-Lafoz et al. find that myocardin-related transcription factors (MRTF) are “double agents.” On one hand, MRTFs support tumor progression and metastasis, but on the other hand, high expression boosts CTL and natural killer–cell activation, an effect enhanced by anti-CTLA4 therapy. High MRTF expression also alters the rigidity of the tumor cell F-actin cytoskeleton, a mechanical change that renders the tumor cells more susceptible to elimination. The data bring to light “mechanical” changes that can occur that allow for improved immunosurveillance and tumor killing.Tello-Lafoz M, …, Er EE. Immunity 2021 Mar 22. DOI: 10.1016/j.immuni.2021.02.020.CD161 on T cells is inhibitory (T/NK-cell CD161 IHC; from Fig. 2F of Dorfeshan et al., Biomed Res Int 2013)T cells play a vital role in the efficacy of immunotherapies. Using single-cell RNA sequencing, Mathewson et al. analyze tumor-infiltrating T cells in patients with glioma. They identify clonal CD8+ T cells coexpressing cytotoxic programs and natural killer (NK) cell–associated genes, including CD161 (encoded by KLRB1). CD161 is identified as an inhibitory receptor that limits T cell–mediated tumor killing. Inactivation of KLRB1 or blockade of CD161 restores T-cell killing of glioma targets in vitro and in vivo. These data point to CD161 and other NK cell–associated receptors (expressed by T cells) as potential immunotherapeutic targets.Mathewson ND, …, Wucherpfennig KW. Cell 2021 Mar 4;184:1281–98.e26.Bacteria-derived peptides can be presented by tumor cells (by Moustafa Abdou via Ask Hematologist/Understand Hematology)Bacteria are associated with some cancers and have a role in modulating immune function. Kalaora et al. investigate whether bacterial antigens are expressed on melanoma HLA molecules. More than 250 bacteria-derived peptides, originating from 41 bacterial species, are identified. A subset of these peptides are not only presented by HLA-I/II in different tumors within the same patient but also found across samples from different patients. The peptides presented by tumor cells are immunogenic and activate tumor-infiltrating lymphocytes ex vivo, providing further insight into the impact of bacteria on antitumor immunity.Kalaora S, …, Samuels Y. Nature 2021 Apr 1;592:138–43.3-D rendering of a neutrophil (from Blausen.com staff via Wikimedia Commons)Microrobots controlled by rotating magnetic fields have potential to allow precise therapeutic targeting of cancers. However, current microrobots are susceptible to immune clearance and cannot efficiently penetrate biological barriers such as the blood–brain barrier. Zhang et al. show these challenges can be addressed using neutrophil-based microrobots, referred to as “neutrobots.” Neutrobots are made in three steps: first, synthesis of nanogels loaded with hydrophobic Fe3O4 nanoparticles and paclitaxel; second, coating of the nanogels with the outer membrane of Escherichia coli; and third, phagocytosis of the coated nanogels by neutrophils. The neutrobots accurately deliver paclitaxel in a postoperative orthotopic glioma model, increasing survival, thereby highlighting the therapeutic potential of neutrobots.Zhang H, …, He Q. Science Robotics 2021 Mar 24;6:eaaz9519.