IRF8 maintains commitment to a cDC1 phenotype (from CCCOnline via Creative Commons).Conventional type 1 dendritic cells (cDC1) have a critical role in antitumor immunity. The transcription factor interferon regulatory factor 8 (IRF8) is known to be involved in cDC1 development, but now Lança et al. show that it also is required to maintain cDC1 identity and function. Irf8 deletion in committed cDC1 leads to transcriptional and functional reprogramming of the cells to a conventional type 2 dendritic cell (cDC2)-like state. Mechanistically, this is associated with chromatin remodeling and loss of the cDC1 epigenetic landscape. The data provide new insight into the biology of cDC1, which directly impacts understanding of cancer immunology.Lança T, …, Agace WW. Immunity 2022 July 12;55:1431–47.E11.α1 homotrimeric collagen promotes an immunosuppressive tumor microenvironment (from Wikimedia Commons).In contrast to fibroblast-derived type I collagen (Col1), the structure and role of tumor-derived Col1 is largely unknown. Chen et al. find that human and mouse pancreatic cancer cells exclusively produce homotrimeric Col1 composed of α1 subunits, whereas fibroblasts produce heterotrimeric Col1 composed of both α1 and α2 subunits. Genetic suppression of Col1 production reduces tumor progression, induces a shift in gut- and tumor-resident microbial composition, promotes microbiome-dependent and -independent proinflammatory tumor immune infiltration, and increases sensitivity to anti–PD-1. These results implicate homotrimeric Col1 in generating a broadly immunosuppressive tumor microenvironment.Chen Y, …, Kalluri R. Cancer Cell 2022 July 21;40:818–34.E9.γδ T-cell subsets can have opposite roles in CRC (by Gregory Maxwell via Wikimedia Commons).The role of γδ T cells in the tumor microenvironment (TME) is not fully elucidated. Reis et al. find that γδ T cells in colorectal cancer (CRC) have distinct phenotypes depending on localization. The authors identify both tumor-promoting and antitumor γδ T-cell subsets, each with distinct Vγδ gene usage. Alterations that occur in these subsets as a result of treatment are demonstrated to affect CRC progression, emphasizing that broadly targeting γδ T cells should be performed with caution and that fine-tuning targeted therapy to specific subsets may be more efficacious.Reis B, …, Mucida D. Science 2022 July 14;377:276–84.TLSs could be a biomarker of response to pembrolizumab (by Fvasconcellos via Wikimedia Commons).Efficacy of immune checkpoint inhibitors (ICIs) is limited. This phase 2 study (PEMBROSARC) tested pembrolizumab (anti–PD-1) combined with low-dose cyclophosphamide in patients with advanced soft-tissue sarcoma (STS). By evaluating data from patients based on tertiary lymphoid structure (TLS) presence, authors found that TLS-enriched tumors, as well as those having high infiltration of plasma cells and dendritic cells into the tumor microenvironment, associate with improved outcome. These data highlight TLSs as predictive biomarkers that could potentially be used for selecting STS patients to be treated with anti–PD-1.Italiano A, …, Fridman WH. Nat Med 2022 May 26;28:1199–1206.A new computational model identifies tumor-resilient T cells (from rawpixel).To answer the question, “How can we identify CD8+ T cells able to elicit efficient antitumor responses?” Zhang et al. developed a computational model called Tres, for tumor-resilient T cell. Tres, which uses single-cell RNA sequencing data, reliably predicts patient response to immune checkpoint inhibitors and adoptive-cell therapies. FIBP, which encodes FGF1 intracellular binding protein, is the top negative marker of T-cell antitumor efficacy identified using Tres. Knocking out Fibp in CD8+ T cells enhances their ability to kill tumor cells in vitro and limits tumor growth in an in vivo model of adoptive-cell therapy. The data highlight how Tres can identify biomarkers of response to immunotherapy and new targets for therapeutic intervention.Zhang Y, …, Jiang P. Nat Med 2022 May 2;28:1421–31.A novel implantable device allows for multiplexed testing of therapeutic agents in the TME (by Bb3cxv from Wikimedia Commons).Evaluating novel chemotherapy/immunotherapy combination treatments traditionally relies on tumor-bearing mouse models, which can be time-intensive, laborious, and challenging to apply to broad patient populations. Tatarova et al. developed an intratumoral implantable device that releases up to 18 drug formulations separated spatially, allowing for multiplexed in vivo tumor microenvironment (TME) analyses. A panel of treatments delivered to a murine breast cancer model identifies a triple combination therapy (panobinostat, venetoclax, and CD40-agonist) that targets cancer stem cells and promotes dendritic cell activity in the TME. The work highlights the implantable drug-delivery system as a method to rapidly design and evaluate TME-targeting drug combinations in situ.Tatarova Z, …, Gray JW. Nat Biotechnol 2022 July 4. DOI:10.1038/s41587-022-01379-y.
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