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

LILRB4 is an inhibitory receptor expressed by many immune cells; its role in antitumor immunity is not well understood. Using mass cytometry, Sharma et al. find that LILRB4 is expressed highly in the tumor microenvironment (TME) on regulatory T cells, exhausted T cells, and tumor-associated macrophages with an immunosuppressive phenotype. Tumor growth in models of melanoma, pancreatic cancer, and colorectal cancer is reduced in LILRB4^−/− mice and mice treated with an LILRB4-specific antibody. This is associated with a switch from an immunosuppressive TME phenotype to an antitumor phenotype, suggesting LILRB4 as a potential new target for cancer immunotherapy.

Sharma N, …, Allison JP. J Exp Med 2021 May 11;218:e20201811.

Terminally exhausted CD8⁺ tumor-infiltrating lymphocytes (TIL) are not responsive to immune checkpoint blockade. Guo et al. show that a half-life–extended IL10–Fc fusion protein reinvigorates terminally exhausted CD8⁺ TILs in mice by promoting pyruvate- and mitochondrial pyruvate carrier–dependent oxidative phosphorylation. This metabolic reprogramming of the terminally exhausted CD8⁺ TILs enhances the expansion and cytotoxic antitumor effector functions of the cells. Half-life–extended IL10–Fc synergizes with adoptive T-cell therapy in three mouse models of established solid tumors, suggesting that it could provide a new approach to enhance current cancer immunotherapies.

Guo Y, …, Tang L. Nat Immunol 2021 May 24;22:746–56.

The mechanisms regulating type 1 conventional dendritic cell (cDC1) acquisition of tumor antigens for cross-presentation to CD8⁺ T cells are not well characterized. Giampazolias et al. find that secreted gelsolin (sGSN) impairs F-actin binding to DNGR-1 (CLEC9A) on cDC1s. This decreases DNGR-1 recognition of dead cells and the subsequent cross-presentation of dead cell–associated antigens. Tumor growth is reduced in mice lacking sGSN because of increased DNGR-1–dependent cross-presentation of tumor antigens. In The Cancer Genome Atlas analysis, low intratumoral levels of sGSN associate with signatures of antitumor immunity and improved survival, suggesting sGSN contributes to cancer immune evasion and is a potential target for cancer immunotherapy.

Giampazolias E, …, Reis e Sousa C. Cell 2021 Jun 2. DOI: 10.1016/j.cell.2021.05.021.

Identifying ways to generate cells more efficiently and rapidly is important for expanding the uses of adoptive cell therapy (ACT) for cancer. Bozza et al. show that using DNA nanovectors, named nano-S/MARt vectors, can efficiently transform T cells to persistently express transgenes. They show the platform can be used to generate chimeric antigen receptor (CAR) T cells and develop a protocol to generate these cells at clinical scale. The nanovectors are nonintegrating and nonimmunogenic, and contain only sequences approved for clinical use, with no viral components. The data highlight a new platform to rapidly and safely generate engineered cells for ACT.

Bozza M, …, Harbottle RP. Sci Adv 2021 Apr 14;7:eabf1333.

The mechanisms underlying antitumor innate immune responses are not well known. Cui et al. find that human, not mouse, neutrophils release ELANE (neutrophil elastase) that preferentially kills cancer cells in the tumor microenvironment. ELANE not only induces tumor cell death, resulting in tumor growth control, but also mediates CD8⁺ T cell–dependent systemic effects. The data support development of human ELANE-targeting/enhancing therapies as a broad anticancer treatment.

Cui C, …, Becker L. Cell 2021 Jun 10;184:3163–77.e21.

The mechanisms by which tumor cells escape the immune system are not fully understood. By using CRISPR-Cas9 screens, Griffin et al. identify chromatin regulators involved in tumor immune exclusion and immune checkpoint blockade (ICB) resistance. SETDB1, an H3K9 methyltransferase, is amplified in human tumors and negatively correlates with immune-associated signatures. Mechanistically, SETDB1 targets multiple regulatory domains that are rich in transposable elements, including those containing immune-related genes. Loss of the protein can induce cytotoxicity by T cells and sensitizes tumors to ICB. The study highlights an epigenetic checkpoint that could be a potential therapeutic target in cancer.

Griffin GK, …, Bernstein BE. Nature 2021 May 5. DOI: 10.1038/s41586-021-03520-4.