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

Abstract

Modulating RNA splicing can augment antitumor T-cell responses (by Srosenbe via Wikimedia Commons)Altered RNA splicing in cancer cells can give rise to neoantigens, but it is unclear whether this is clinically relevant and therapeutically targetable. Using B16-F10 and MC38 tumor models, Lu et al. find several compounds that modulate RNA splicing can inhibit tumor growth and improve responses to anti-PD1 checkpoint blockade. These effects are dependent on T cells and MHC class I peptide presentation. Neoepitopes induced by pharmacologic modulation of RNA splicing in B16-F10 cells can trigger antitumor T-cell responses in mice. The data suggest potential new approaches to enhancing cancer immunotherapy.Lu SX, …, Bradley RK. Cell 2021 Jul 22;184:4032–47.e31.Arming CAR T cells with BATF enhances efficacy (from Spezadams via Wikimedia Commons)The transcriptional networks underlying T-cell exhaustion, including exhaustion in CAR T cells, are not fully known. Seo et al. show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) act in a cooperative manner to offset T-cell exhaustion. Overexpression of BATF in CAR T cells increases cell persistence and cytokine production and decreases expression of inhibitory receptors and exhaustion-related markers. These effects are dependent on interactions between BATF and IRF4. The data highlight potential therapeutic targets to improve CAR T-cell therapy.Seo H, …, Hogan PG. Nat Immunol 2021 Aug 1;22:983–95.TILs with differing specificities have different functional states (from Brandon Dilbeck via Wikimedia Commons)Understanding of the relationship between the functional state of tumor-infiltrating lymphocytes (TIL) and the specificity of their TCRs is limited, but advances in single-cell technology are changing this. Using such technologies, Caushi et al. show that non–small cell lung cancer TILs with TCRs specific for mutation-associated neoantigens (MANA) have a unique transcriptional profile that is largely characteristic of tissue-resident memory cells and that MANA-specific T cells from tumors nonresponsive to anti-PD1 express significantly reduced levels of genes associated with T-cell dysfunction. Oliveira et al. show that melanoma-reactive TILs are predominantly in an exhausted state and only rarely acquire memory properties, and that disease persistence correlates with persistence of exhausted melanoma-reactive cells in peripheral blood. These data will inform further development of cancer immunotherapy.Caushi JX, …, Smith KN. Nature 2021 Aug 5;596:126–32.Oliveira G, …, Wu CJ. Nature 2021 Aug 5;596:119–25.A targeted radionuclide and checkpoint inhibition combination enhances antitumor immunity (by MichaelFrey via Wikimedia Commons)External beam radiotherapy enhances responses to immune checkpoint blockade (ICB) in preclinical models. Patel et al. show that a targeted radionuclide therapy comprising the alkylphosphocholine analogue NM600 chelated to yittrium-90 (90Y) enhances responses to ICB in mouse models of melanoma, neuroblastoma, and breast cancer without causing toxicity to normal tissues. The 90Y-NM600 plus ICB combination increases immune-cell infiltration into the tumor, and production of proinflammatory cytokines and clonal expansion of CD8+ T cells in the tumor, highlighting the immunologic mechanisms behind this potential new therapeutic combination.Patel RB, …, Morris ZS. Sci Transl Med 2021 Jul 14;13:eabb3631.TFR cells can suppress antitumor responses induced by ICB (from Fig. 1C of Rodriguez and Engelhard, Cancer Immunol Res 2020)The mechanisms behind the effects of immune checkpoint blockade (ICB) are not completely understood. Eschweiler et al. show that follicular regulatory T (TFR) cells are present in tumor-associated tertiary lymphoid structures (TLS) and that they are more suppressive than regulatory T cells. Anti-PD1 can increase the number of TFR cells in tumors, and administration of anti-CTLA4 to deplete regulatory cells prior to anti-PD1 improves treatment efficacy in mice and humans.Eschweiler S, …, Vijayanand P. Nat Immunol 2021 Aug 1;22:1052–63.β2M can accumulate in the tumor microenvironment (β2M staining, from Fig. 1A of Roemer et al., Cancer Immunol Res 2016)β2-microglobulin (β2M) concentrations increase during progression of multiple myeloma (MM), but β2M's role in disease is not well-known. Hofbauer et al. find that MM-associated macrophages can phagocytose β2M, which then leads to NLRP3-mediated inflammasome activation. The resulting cytokine secretion and inflammation contribute to MM severity. Inhibition of the inflammasome or related cytokines ameliorates disease in a mouse model of MM, thus highlighting potential therapeutic targets for the treatment of MM.Hofbauer D, …, Bruns H. Immunity 2021 Jul 20. DOI: 10.1016/j.immuni.2021.07.002.