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

Abstract

CAR T cells can be engineered to overcome antigen loss (from Fig. 2C of Landoni et al., Cancer Immunol Res 2021)One factor limiting chimeric antigen receptor (CAR) T-cell therapy efficacy against solid tumors is CAR antigen loss. Johnson et al. show that engineering CAR T cells to express the RNA RN7SL1 increases their antitumor efficacy in multiple models. RN7SL1 enhances CAR T-cell expansion and effector-memory differentiation, and also is transferred in extracellular vesicles to other immune cells that then promote activation of endogenous T cells that can reject solid tumors with CAR antigen loss. By testing various combinations of CAR constructs, Hirabayashi et al. find that T cells engineered to be dual targeting—with each CAR signaling through a different costimulatory endodomain, only one of which includes a CD3ζ-chain—provide the most effective antitumor effects and prevent antigen loss.Johnson LR, …, Minn AJ. Cell 2021 Sep 16;184:4981–95.e14.Hirabayashi K, …, Dotti G. Nat Cancer 2021 Sep 23;2:904–18.Local delivery of cytokine-ending mRNA could improve immunotherapy efficacy (by Gwillhickers via Wikimedia Commons)How to effectively deliver immunotherapy locally to tumors remains a challenge. Hotz et al. test the intratumoral delivery of a mixture of mRNAs encoding four cytokines/cytokine fusion proteins (IL12 single chain, IFNα4, GM-CSF, and IL15 sushi) in multiple tumor models. They find the treatment effectively activates antitumor immunity and induces immune memory; therapeutic effects are observed for primary, distant, and metastatic tumors. Combining the mRNA mixture with immune checkpoint blockade further enhances therapeutic benefit. The data suggest that this treatment strategy has the potential to improve current immunotherapy regimens, and it is now being tested in clinical trials.Hotz C, …, Wiederschain D. Sci Transl Med 2021 Sep 8;13:eabc7804.Pancreatic adenocarcinoma frequently evades the immune system (by Min Yu via NIH Flickr)Pancreatic adenocarcinoma (PDAC) is largely refractory to immunotherapy. Freed-Pastor et al. have developed organoid models of the subset of PDACs they predict to have high-affinity neoantigens and find that some of these organoids evade the immune system after transplantation into immune-competent mice. Immune-evasive organoids and human PDACs are infiltrated with dysfunctional neoantigen-specific CD8+ T cells and have high CD155 expression. Blockade of CD155/TIGIT signaling, together with anti–PD-1 blockade and CD40 agonism, limited immune evasion and CD40-agonist resistance in the mice, identifying a potential combination therapeutic strategy for PDAC.Freed-Pastor WA, …, Jacks T. Cancer Cell 2021 Oct 11;39:1342–60.e14.A CRISPR screen links tumor suppressor genes and the adaptive immune system (by Ernesto del Aguila III via NIH Flickr)Genetic screens for drivers of tumorigenesis are often conducted using systems that do not account for the complexity of the tumor microenvironment, including pressure exerted by the immune system. By performing transcriptome-wide CRISPR screens in mouse tumor models using animals with and without functional adaptive immunity, Martin et al. find an enrichment for loss of tumor suppressor genes as a requirement for tumor growth in the presence of an adaptive immune system. Loss of one tumor suppressor gene, GNA13, increases recruitment of tumor-associated macrophages by enhancing CCL2 secretion. These data highlight potential new functions for tumor suppressor genes that could be harnessed for immunotherapy.Martin TD, …, Elledge SJ. Science 2021 Sep 17;373:1327–35.Engineering IL-2 to be a partial agonist can enhance adoptive cell therapy (by Emw from Wikimedia Commons)IL-2 is often used in the generation of T cells for adoptive cell therapy because it promotes T-cell expansion. However, it also induces terminal differentiation and expression of coinhibitory molecules, limiting therapeutic efficacy. Mo et al. identify an IL-2 partial agonist, H9T, that promotes CD8+ T–cell expansion but not terminal differentiation; rather, it drives transcriptional, epigenetic, and metabolic profiles that restrict T-cell exhaustion and maintain a stem cell–like state. T-cell receptor transgenic T cells and CAR T cells expanded with H9T show enhanced antitumor activity in mice compared with cells expanded in IL-2, highlighting the potential for engineering cytokines to increase adoptive cell therapy efficacy.Mo F, …, Leonard WJ. Nature 2021 Sep 23;597:544–8.A feedback loop facilitates tumor metastasis (by AleXXw via Wikimedia Commons)Tumor cells use various mechanisms to disseminate from the primary tumor to a metastatic site. Morrissey et al. show that tumor-derived exosomes drive polarization of macrophages in the premetastatic niche to an immune-suppressive phenotype, thereby promoting tumor metastasis. Macrophage interaction with tumor-derived exosomes leads to upregulation of PD-L1 and metabolic alterations, which act to further increase macrophage PD-L1 expression. The data highlight a feedback loop that potentiates immune suppression and identifies tumor-derived exosomes, macrophages, and metabolism-related factors as key players in the process.Morrissey SM, …, Yan J. Cell Metab 2021 Oct 5;33:2040–58.e10.