Knockout of RASA2 enhances T-cell antitumor function (from Public Domain Vectors)Several immunosuppressive mechanisms limit the efficacy of adoptive T-cell therapies. Carnevale et al. performed six genome-wide CRISPR–Cas9 knock-out screens for regulators of T-cell resistance to immunosuppression by inhibitors of calcium and calcineurin, TGFβ, and regulatory T cells, identifying a role for RAS p21 protein activator 2 (RASA2) in each case. Knocking out RASA2A in human T cells, including T-cell receptor (TCR) and chimeric antigen receptor (CAR)–engineered T cells, enhances their antitumor function in vitro and in xenograft models of melanoma, osteosarcoma, and acute lymphoblastic leukemia. The data suggest ablation of RASA2 may enable the generation of more efficacious adoptive T-cell therapies.Carnevale J, …, Marson A. Nature 2022 August 24;609:174–82.CD62L+ TPEX cells mediate responses to anti–PD-1 (from NIAID via NIH Flickr)Precursors of exhausted T (TPEX) cells, characterized by expression of TCF1, mediate responsiveness to anti–PD-1. Following single-cell RNA sequencing of TPEX cell–enriched CD8+ T cells from mice chronically infected with lymphocytic choriomeningitis virus (LCMV), Tsui et al. stratify TPEX cells by expression of Sell, which encodes CD62L. The transcription factor MYB is required for the development of CD62L+ TPEX cells, which show enhanced capacity for self-renewal, multipotency, and long-term proliferation compared with CD62L– TPEX cells. CD62L+ TPEX cells are pivotal for responsiveness to anti–PD-1 in mice chronically infected with LCMV. Thus, it is vital that we better understand their role in T cell–mediated cancer immunotherapy.Tsui C, …, Kallies A. Nature 2022 August 17;609:354–60.iNKT cells outperform other cell therapies (from Todd van Hoosear via Flickr)The immune suppressive tumor microenvironment (TME) can curb responses to an array of cell-based therapies. Delfanti et al. demonstrate the utility of T-cell receptor (TCR)–engineered invariant natural killer T (iNKT) cells to overcome immune-suppressive barriers in the TME. The engineered iNKT cells act as bispecific effectors, bridging CD1d to MHC-restricted antigens on tumor cells, while also maintaining their known TME-modulating functions. Treatment with these cells outperforms nontransduced iNKT cells and CD8+ T cells expressing the same TCR, and efficacy can be boosted with addition of an iNKT-cell agonist. These data show that TCR-engineered iNKT cells could be a potential cell-based therapy for patients with cancer.Delfanti G, …, Casorati G. Sci Immunol 2022 August 19;7:sciimmunol.abn65.Targeting COX2+ fibroblasts can improve antitumor responses (from go digital via Flickr).How the premetastatic niche develops and what cell types in the metastasis-supporting organ are involved has not been fully elucidated. Gong et al. identify a subset of cyclooxygenase 2–positive (COX-2+) lung fibroblasts that modulate the function of multiple myeloid cell subsets, rendering them dysfunctional or immune suppressive. This process is enhanced by neutrophil-derived IL1β produced because of tumor-associated inflammation. In breast cancer models, targeting the COX2 pathway in these fibroblasts improves immunotherapy efficacy and reduces lung metastasis, highlighting how understanding the microenvironment of the premetastatic niche can facilitate identification of therapeutic targets to boost antitumor responses.Gong Z, …, Ren G. Immunity 2022 July 30;55:1483–1500.E9.In situ generation of CAR-macrophages effectively prevent GBM recurrence (from Christaras A via Wikimedia Commons)Recurrence of glioblastoma multiforme (GBM) after surgical resection is driven by residual glioma stem cells (GSC). Chen et al. developed a cavity-injectable hydrogel embedded with macrophage-targeted nanoporter particles that they used to deliver plasmids encoding a CD133-directed chimeric antigen receptor (CAR) to macrophages in situ following tumor resection in preclinical models. The CAR+ macrophages target GSCs and show antitumor activity in vitro and in vivo, including preventing recurrence of surgically resected GBM in an orthotopic patient-derived xenograft model. These findings suggest that the injectable CAR-macrophage platform may be an effective therapeutic strategy to improve long-term survival of GBM patients.Chen C, …, Jiang X. Sci Trans Med 2022 Aug 3;14:scitranslmed.abn1128.Tumor-reactive T cells exhibit signatures of activation indicative of their TCR avidity (from Takuma-sa via Wikimedia Commons)The impact of T-cell receptor (TCR) avidity on T-cell antitumor activity remains unclear. Through adoptive transfer of ultra-low (<1000) numbers of T cells with OVA-specific TCRs of varying avidity into mice bearing OVA-expressing tumors, Purcarea et al. found that tumor-reactive T cells in tissues outside of tumors express PD-1 proportional to the avidity of their TCR and to their protective capacity. Tumor-infiltrating and peripheral T cells isolated from human melanoma patients exhibit gene expression and phenotypic signatures of ex vivo TCR functionality and cytotoxicity, altogether presenting molecular markers of highly active tumor-specific T cells.Purcarea A, …, Schober K. Sci Immunol 2022 August 12;7:sciimmunol.abm207.
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