Lurbinectedin is an approved second-line treatment for small-cell lung cancer (SCLC). SCLC clinical trials combining lurbinectedin with PD-L1 blockade are currently ongoing. However, the immunomodulatory effects of lurbinectedin remain largely unknown. In this study, we demonstrate that lurbinectedin treatment activates the STING pathway, which increases interferon (IFN) signaling, pro-inflammatory chemokines, and major histocompatibility complex class I (MHC-I) in SCLC models. Lurbinectedin treatment augments the anti-tumor immune response of PD-L1 blockade with significant tumor regression in first-line and maintenance settings in SCLC mouse models. In vivo, lurbinectedin treatment increases CD8+ T cells and M1 macrophages and decreases immunosuppressive M2 macrophages. STING and CD8 depletion reverses the anti-tumor response. Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

CD4+CD25+Foxp3+ regulatory T cells (Treg) have been implicated in pain modulation in various inflammatory conditions. However, whether Treg cells hamper pain at steady state and by which mechanism is still unclear. From a meta-analysis of the transcriptomes of murine Treg and conventional T cells (Tconv), we observe that the proenkephalin gene (Penk), encoding the precursor of analgesic opioid peptides, ranks among the top 25 genes most enriched in Treg cells. We then present various evidence suggesting that Penk is regulated in part by members of the Tumor Necrosis Factor Receptor (TNFR) family and the transcription factor Basic leucine zipper transcription faatf-like (BATF). Using mice in which the promoter activity of Penk can be tracked with a fluorescent reporter, we also show that Penk expression is mostly detected in Treg and activated Tconv in non-inflammatory conditions in the colon and skin. Functionally, Treg cells proficient or deficient for Penk suppress equally well the proliferation of effector T cells in vitro and autoimmune colitis in vivo. In contrast, inducible ablation of Penk in Treg leads to heat hyperalgesia in both male and female mice. Overall, our results indicate that Treg might play a key role at modulating basal somatic sensitivity in mice through the production of analgesic opioid peptides.
© 2024, Aubert et al.

Th9 cells are powerful effector T cells for cancer immunotherapy. However, the underlying antitumor mechanism of Th9 cells still needs to be further elucidated. Here, we show that Th9 cells express high levels of not only IL-9, but also IL-24. We found that knockout of Il24 gene in Th9 cells promotes Th9 cell proliferation in vitro, but decreases Th9 cell survival in vitro and in vivo. Interestingly, knockout of Il24 gene in Th9 cells decreases the tumor-specific cytotoxicity of Th9 cells in vitro. In addition, immunotherapy with Il24 knockout Th9 cells exhibit less tumor inhibition than regular Th9 cells in mouse tumor models. We found that inhibition of Foxo1 by a specific inhibitor downregulates IL-24 expression in Th9 cells and decreases Th9 cell antitumor efficacy in vivo. Our results identify IL-24 as a powerful antitumor effector of Th9 cells and provide a target in Th9 cell-mediated tumor therapy.
© 2023 The Authors.

Progressive loss of effector functions, especially IFN-γ secreting capability, in effector memory CD8+ T (CD8+ TEM ) cells plays a crucial role in asthma worsening. However, the mechanisms of CD8+ TEM cell dysfunction remain elusive. Here, we report that S100A4 drives CD8+ TEM cell dysfunction, impairing their protective memory response and promoting asthma worsening in an ovalbumin (OVA)-induced asthmatic murine model. We find that CD8+ TEM cells contain two subsets based on S100A4 expression. S100A4+ subsets exhibit dysfunctional effector phenotypes with increased proliferative capability, whereas S100A4- subsets retain effector function but are more inclined to apoptosis, giving rise to a dysfunctional CD8+ TEM cell pool. Mechanistically, S100A4 upregulation of mitochondrial metabolism results in a decrease of acetyl-CoA levels, which impair the transcription of effector genes, especially ifn-γ, facilitating cell survival, tolerance, and memory potential. Our findings thus reveal general insights into how S100A4+ CD8+ TEM cells reprogram into dysfunctional and less protective phenotypes to aggravate asthma.
© 2022 Wiley-VCH GmbH.

Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8+ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.