A Sampling of Highlights from the Literature

Abstract

The timing of immune interactions modulates antitumor responses (from LetsgomusicStyle via Wikimedia Commons)Immune cell interactions are critical to mounting effective antitumor responses. Wang et al. show that antitumor responses are coordinated by dendritic cell (DC)–CD8+ T-cell interactions and that expression of key circadian rhythm genes governs immune function, which is also affected by the time of day (day vs. night). Cervantes-Silva et al. reveal that DC antigen presentation is also dependent on expression of circadian rhythm genes, which regulate DC mitochondrial morphology and metabolism, and thus, affect T-cell priming. These studies highlight that induction of antitumor responses is a coordinated, rhythmic process, and a deeper understanding of immune rhythmicity can improve therapeutic strategies.Wang C, …, Scheiermann C. Nature 2022 December 5. DOI:10.1038/s41586-022-05605-0.Cervantes-Silva MP, …, Curtis AM. Nat Commun 2022 December 5;13:7217.IL2 is less active in the acidic tumor microenvironment (from BQUB17-ONadal via Wikimedia Commons)High-dose IL2 is approved for treating melanoma and renal cell carcinoma but is used infrequently because of limited efficacy and systemic on-target toxicity. Gaggero et al. find that the acidic pH of the tumor microenvironment (TME), created as a result of tumor production of lactic acid, reduces IL2 signaling in tumor-infiltrating CD8+ T cells, impairing the efficacy of high-dose IL2 therapy in preclinical models. A mutated IL2 variant (Switch-2) that binds IL2Rα with higher affinity at acidic pH than neutral pH shows enhanced antitumor activity with reduced on-target toxicity in mice. The data provide new insight into physicochemical properties of the TME that can impact immunotherapy efficacy and suggest ways to overcome this.Gaggero S, …, Mitra S. Sci Immuol 2022 December 2;7:eade5686.Eosinophils contrib-ute to the efficacy of ICB (from Blausen Medical via Wikimedia Commons)Understanding the mechanisms behind why immune checkpoint blockade (ICB) is not effective in many patients is key to improving treatment. Blomberg et al. find that eosinophils are enriched in ICB-responding patients with breast cancer. This observation was confirmed in a mouse model, and CD4+ T cells, IL5, and IL33 were identified as the driving factors for eosinophil enrichment. Increased eosinophil infiltration boosts eosinophil-dependent activation of CD8+ T cells, which in turn enhances efficacy of ICB. The data emphasize how immune cells other than T cells are affected by ICB and how they can be critical determinants of treatment efficacy.Blomberg OS, …, Kok M. Cancer Cell 2022 December 15;41:106–123.E10.Antitumor T-cell responses require two steps (from DENI070688 via Wikimedia Commons)Understanding T-cell differentiation can reveal insights into the mechanisms behind effective antitumor responses. Prokhnevska et al. demonstrate that T cells are activated via two key steps: first, initial priming and differentiation into a TCF-1+ stemlike phenotype in tumor-draining lymph nodes (TDLN); and second, acquisition of an effector program after infiltrating the tumor microenvironment (TME). Effector programming of CD8+ T cells is dependent on co-stimulation from antigen-presenting cells in the TME, as opposed to in the TDLNs. This process differs from canonical priming/activation of CD8+ T cells in other contexts and adds to our understanding of how T cells mount responses to cancer.Prokhnevska N, …, Kissick H. Immunity 2022 December 28;56:107–124.Eosinophils contribute to the efficacy of ICB (from Boghog2 via Wikimedia Commons)IL22 is known to facilitate tumorigenesis. Two new studies identify mechanisms by which IL22 promotes tumor metastasis and suggest the cytokine as a therapeutic target for preventing metastasis. Giannou et al. find that mice lacking IL22 and mice treated with an IL22-specific blocking antibody are protected from liver metastasis in a colorectal cancer model. Mechanistically, IL2 from liver-resident iNKT17 cells acts on endothelial cells, promoting cancer cell extravasation into the liver. In mouse models of lung and breast cancer, Briukhovetska et al. show that T helper–cell production of IL22 induces overexpression of CD155 on tumor cells. Binding of CD155 to CD226 on natural killer (NK) cells causes CD266 internalization and impaired NK-cell function, promoting metastasis.Giannou AD, …, Huber S. Immunity 2023 January 10;56:125–142.E12.Briukhovetska D, …, Kobold S. Immunity 2023 January 10;56:143–161.E11.Engineered live cancer cells can promote effective antitumor immunity (from Rita Elena Serda via NIH Flickr)The use of inactivated tumor cells as a therapeutic vaccine has been shown to provide limited clinical benefit. Chen et al. show that engineering live cancer cells to secrete IFNβ and GM-CSF, to be resistant to IFNβ, and to have a double kill switch (HSV1 thymidine kinase and rapamycin-activated caspase 9) yields therapeutic cancer cell–based vaccines that induce long-term antitumor immunity and improve survival in several preclinical models. The translatability of this approach is highlighted by the observation that similar engineering of an established human glioblastoma cell line yields a vaccine that reduces tumor growth and improves survival in a humanized model.Chen K-S, …, Shah K. Sci Trans Med 2023 January 4;14:eabo4778.