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

Dendritic cells (DCs) induce antitumor T-cell responses in tumor-draining lymph nodes (LNs), yet how antigen is disseminated between the various DC populations is unknown. Migratory CD103⁺ DCs (cDC1s) or CD11b⁺ DCs (cDC2s) package tumor antigens in membrane-bound vesicles and transport the antigens to LNs in a CCR7-mediated manner. cDC1s and cDC2s then pass this packaged antigen to CD8α⁺ DCs via cell-to-cell exchange of membrane material in the absence of exosomes. Migratory DCs in the LNs lead to CD4⁺ T-cell responses, and CD8α⁺ DCs lead to CD8⁺ T-cell responses. This work clarifies first steps in DC-mediated antitumor responses.

Ruhland MK, …, Krummel MF. Cancer Cell 2020 Jun 8;37:786–99.E5.

Type 1 conventional DCs (cDC1s) can be dysregulated in cancer. Using a KPC mouse model, Lin and colleagues show that cDC1s become progressively dysfunctional and undergo increased apoptosis beginning in early stages of pancreatic cancer. cDC1 maturation is also reduced, resulting in suboptimal T-cell priming. By neutralizing IL6, cDC1 apoptosis can be reversed, and alternatively administration of Flt3 ligand and agonistic anti-CD40 synergistically rescues responses via both decreasing cDC1 apoptosis and promoting maturation, thereby enhancing T-cell priming. These data highlight an early DC dysfunction in pancreatic cancer that contributes to disease progression and demonstrate how restoring cDC1 function could be a potential therapeutic strategy.

Lin JH, …, Vonderheide RH. J Exp Med 2020 Aug 3;217:e20190673.

Fat mass and obesity-associate protein (FTO), an RNA N6 methyladenosine demethylase, is oncogenic, thus its inhibition might be an effective anticancer treatment. Using drug compound screening, two NCI compounds are found to bind FTO and inhibit its demethylase activity. These inhibitors block FTO binding to its mRNA targets, suppressing FTO downstream signaling, inducing cell-cycle inhibition and acute myeloid leukemia (AML) apoptosis, and inhibiting LILRB4, an immune checkpoint gene. FTO inhibition slows AML tumor growth by sensitizing AML cells to T-cell killing in a LILRB4-mediated manner. Thus, FTO inhibition may be a viable treatment for AML patients.

Su R, …, Chen J. Cancer Cell 2020 Jul 13;38:79–96.E11.

Finding alternatives to improve cytokine immunotherapy is needed both to increase therapy efficacy and to reduce toxicity in patients with cancer. Zhou and colleagues demonstrate that a high-affinity IL18 decoy receptor, IL18BP, is increased in mouse and human tumors and can hinder IL18 responses. By engineering a “decoy-resistant” IL18, signaling is maintained in the presence of IL18BP and enhances antitumor responses by promoting polyfunctional CD8⁺ T cells, decreasing T-cell exhaustion, and increasing maturation and function of NK cells. Thus, targeting the IL18 signaling pathway can boost antitumor responses.

Zhou T, …, Ring AM. Nature 2020 Jun 24. DOI: 10.1038/s41586-020-2422-6.

Senescent cells demonstrate cell-cycle arrest and a secretory program that supports an immune suppressive microenvironment. Urokinase-type plasminogen activator receptor (uPAR) is identified as a cell surface and secreted biomarker of senescent cancer cells and fibrotic tissue. uPAR-specific CAR T cells kill senescent target cells and inhibit induction of liver fibrosis. uPAR-specific CAR T cells are a bona fide senolytic agent that can inhibit various senescence-related maladies.

Amor C, …, Lowe SW. Nature 2020 Jun 17;583:127–32.

Hypoxia is a common feature of the tumor microenvironment, and upregulation of HIF-1α is a way for cells to adapt. Through transcriptional analysis of tumor-infiltrating NK cells, Ni and colleagues find conditional deletion of NK-cell HIF-1α, in concert with myeloid cell IL18 production, reduces tumor growth in mice by enhancing NK-cell activation, metabolism, and function. Low HIF-1α expression associates with increased IFNG expression in human tumoral NK cells, a signature that correlates with improved survival in patients with solid tumors. Targeting HIF-1α is a potential strategy for boosting antitumor responses.

Ni J,…, Cerwenka A. Immunity 2020 Jun 16;52:1075–87.E8.