A Sampling of Highlights from the Literature

Platelet factor 4, a cytokine that polarizes Th1-Treg in tumors (from Emw via Wikimedia Commons)A subset of Th1 cells expressing Foxp3, named Th1-Tregs, have been identified in tumors, but the mechanisms underlying their accumulation in tumors are unclear. Using single-cell and bulk RNA sequencing, Kuratani and colleagues identify the chemokine platelet factor 4 (PF4) as a polarizing factor for Th1-Tregs. PF4 is shown to be made by Arg1+ tumor-associated macrophages, and these cells contribute to lowered antitumoral activity. Genetic deletion or antibody neutralization of PF4 in tumor-bearing mice reduces Th1-Treg frequencies and tumor growth. Targeting of this subset of Tregs, instead of all Tregs, may lead to tumor clearance with limited risk of inducing autoimmunity.Kuratani A, …, Yamamoto M. Science 2024 Nov 22;386,eadn8608.Soluble factors in the ovarian TME have short-range effects (from NCI\Comprehensive Cancer Center of Wake Forest Univ. via NCI Visuals)How secreted factors influence the phenotype and heterogeneity of the ovarian tumor microenvironment (TME) is unclear. To address this, Mollaoglu and colleagues used a spatial functional genomics screen in the ID8 ovarian cancer model, which grows as a heterogeneous mix of clonally distinct tumor lesions, finding that loss of CCL7 promotes an immune-excluded TME that accelerates ovarian tumor growth, whereas loss of IL4 increases sensitivity to anti–PD-1. In both cases, regional loss of the soluble factor is not compensated for by neighboring factor-producing clones, highlighting that chemokines and cytokines have short-range effects that can lead to spatially distinct immune neighborhoods in the TME.Mollaoglu G, …, Brown BD. Cell 2024 Oct 30;DOI:10.1016/j.cell.2024.10.006.Cretostimogene grenadenorepvec is an engineered oncolytic serotype 5 adenovirus (from Thomas Splettstoesser via Wikimedia Commons)For patients with muscle-invasive bladder cancer (MIBC) who are ineligible for chemotherapy, immunotherapies are a promising alternative therapy. Li and colleagues report data from the phase Ib trial NCT04610671 evaluating oncolytic immunotherapy through intravesical delivery of cretostimogene grenadenorepvec combined with anti–PD-1. Among 21 patients, there were no reported dose-limiting toxicities, a 42% complete response rate, and a 1-year recurrence-free survival rate of 70%. Successful clearance of tumors was associated with increased formation of tertiary lymphoid structures within the tumor. The results highlight the potential of this combination therapy for patients with MIBC.Li R, …, Conejo-Garcia JR. Nat Med 2024 Nov 9;DOI:10.1038/s41591-024-03324-9.Data suggest CAR T-cell promise for two additional types of cancer (from Nick Youngson via Alpha Stock Images)Data from two clinical trials show chimeric antigen receptor (CAR) T-cell therapy may be effective beyond B-cell malignancies. In final clinical data from Arm A of the phase I trial NCT04196413, Monje and colleagues report that 9 of 11 patients with H3K27M-mutated diffuse midline glioma who received GD2-targeted CAR T cells intravenously (IV) had clinical or imaging benefit and subsequently received sequential intracerebroventricular (ICV) infusions. As cytokine-release syndrome was dose-limiting following IV administration, subsequent arms will evaluate ICV-only administration. Cwynarski and colleagues report that 4 of 10 patients with peripheral T-cell lymphoma who received TRBC1-targeted CAR T cells in the single-arm phase I/II trial NCT03590574 had complete metabolic response. These preliminary data support continued development of this therapy.Monje M, …, Mackall C. Nature 2024 Nov 13;DOI:10.1038/s41586-024-08171-9.Cwynarski K, …, Pule M.Nat Med2024 Nov 11;DOI:10.1038/s41591-024-03326-7.Fibroblastic reticular cells form structures to organize T cells to efficiently clear tumors (from Jebulon via Wikimedia Commons)Organizing T cells within the tumor microenvironment is essential for efficient antitumoral responses. Onder and colleagues examined how fibroblastic reticular cells (FRCs) aid in the organization of T cells into interconnected T-cell environments (TEs). These TEs include tertiary lymphoid structures and T-cell tracks that emerge in cancer. Using single-cell RNA sequencing and cell fate-mapping in a non–small cell lung cancer model, CCL19-expressing FRCs are shown to be responsible for sustaining these TEs. Loss of FRCs results in reduced antitumoral functions of CD8+ T cells and increases tumor growth. The data suggest targeting FRCs to create environments that enhance T-cell function could improve immunotherapies.Onder L, …, Ludewig B. Cell 2024 Nov 19;DOI:10.1016/j.cell.2024.10.042.Lung-resident alveolar macrophages are a barrier to metastasis (from Nephron via Wikimedia Commons)The mechanisms that keep breast cancer cells that spread to the lungs early in cancer development dormant for long periods are not well characterized. In mouse models, Dalla and colleagues show that lung-resident alveolar macrophages (AM) promote dormancy in breast cancer cells that disseminate to the lungs early in cancer development. This occurs via AM expression of TGFβ2 interacting with TGFβ2III, a specific receptor for TGFβ2, on the disseminated cancer cells. Breast cancer cells that disseminate to the lungs late during cancer development escape AM-induced dormancy by downregulating TGFβRIII. The data provide new insight into barriers to metastasis for potential therapeutic modulation.Dalla E, …, Aguirre-Ghiso JA. Cell 2024 Nov 14;187,6631-6648.e20.