Oncology
Abstract
Adoptive cell therapy (ACT) relies on durable and functional T cells to mediate tumor clearance. Th9 cells are a metabolically fit CD4+ T cell subset with strong persistence but limited cytotoxicity. Here, we identified endomelipeptide A (EpA), a cyclic peptide isolated from Ganoderma lucidum–associated endophytic fungi, as a potent enhancer of Th9 differentiation. EpA promoted a cytotoxic Th9 phenotype with enhanced mitochondrial function and metabolic fitness. Mechanistically, EpA dually targeted ZAP70 and SREBP1, coupling T cell receptor (TCR) signaling activation with lipid metabolism suppression. EpA-treated Th9 cells mediated robust, CD8+ T cell–dependent tumor control and enhanced the efficacy of human Th9 CAR-T therapy in vivo. These findings establish EpA as a distinct cyclic peptide that reprograms Th9 cells and provides a potential approach to boost ACT efficacy.
Authors
Wenli Zhao, Yang Zhou, Yuyang Chen, Yicheng Sun, Jiaxin Tang, Yihan Zhu, Jie Ren, Tianxu Du, Handuo Wang, Yuan Gao, Yu Hu, Ling Jiang, Tomohiko Ohwada, Qi Luo, Enguang Bi
Abstract
EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist Osimertinib (Osi) eventually relapse owing in part to the emergence of drug tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intra-tumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-to-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell lines in which drug naive (DN) cells were rendered OR by chronic exposure to escalating doses of Osi. Co-cultured in vitro or co-injected into mice, paracrine signals from OR cells enhanced the growth and metastatic properties of DN cells. EMT and senescence activated non-overlapping secretomes, and OR cells governed DN cells by undergoing EMT but not senescence. Mechanistically, Osi rapidly increased TGFβ2 levels to initiate EMT, which triggered a Golgi remodeling process that accelerated the biogenesis and anterograde trafficking of secretory vesicles. The pro-tumorigenic activity of OR cells was diminished by depletion of EMT-dependent secreted proteins or the EMT-activating transcription factor ZEB1. These findings identify paracrine mechanisms by which OR cells drive LUAD progression.
Authors
Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique B. Nilsson, John V. Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate V. Grimley, William K. Russell, Chad J. Creighton, Xiaochao Tan, Jonathan M. Kurie
Abstract
Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP-glucuronosyltransferase 2B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduces tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.
Authors
Tingting Feng, Ning Xie, Lin Gao, Qiongqiong Jia, Sonia Kung, Tunc Morova, Yinan Li, Lin Wang, Ladan Fazli, Louis Lacombe, Chantal Guillemette, Eric Lévesque, Nathan A. Lack, Jianfei Qi, Bo Han, Xuesen Dong
Abstract
GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.
Authors
Zheng Zhong, Xinang Cao, Pei-Ju Liao, Raman Sethi, Jeffrey A. Klomp, Clint A. Stalnecker, Jinmiao Chen, Yue Wan, Channing J. Der, David M. Virshup
Abstract
The efficacy of anticancer treatments, including radiotherapy, depends on the activation of type I IFN signaling. However, its regulatory networks and mechanisms remain to be elucidated. Here, we report that tumor cell–intrinsic type I IFN signaling can be transferred to macrophages via secretory autophagy, inducing CXCL9hi macrophages and enhancing CD8+ T cell–mediated antitumor immunity. Mechanistically, K63-linked ubiquitination at the K167 site of phosphorylated STAT2 (p-STAT2) facilitates its binding to LC3B, promoting the loading of p-STAT1 and p-STAT2 into extracellular vesicles and intercellular transference from tumor cells to macrophages, which, however, is suppressed by USP5-mediated STAT2 deubiquitination. Genetic depletion or pharmacological inhibition of USP5 promotes autophagy-dependent unconventional protein secretion of p-STAT1 and p-STAT2, leading to the induction of CXCL9+ macrophages. This process promotes the expression of T cell chemokines and upregulates the antigen presentation machinery, thereby enhancing radiation-induced CD8+ T cell antitumor immunity and radiotherapy efficacy. Our findings reveal a critical role of USP5 in type I IFN–induced antitumor immunity, providing potential targets for improving the efficacy of radiotherapy.
Authors
Jun-Yan Li, Ying-Qing Li, Jia-Hao Dai, Sha Gong, Qing-Mei He, Jie-Wen Bai, Sai-Wei Huang, Ying-Qi Lu, Yu-Fei Duan, Sen-Yu Feng, Xi-Rong Tan, Xiao-Yu Liang, Jun Ma, Rui Guo, Na Liu
Abstract
Authors
Antonio Carlos Tallon-Cobos, Konstantinos Vazaios, Piotr Waranecki, Marliek van Hoesel, Annelisa M. Cornel, Benjamin Schwalm, Norman Mack, Ella de Boed, Jasper van der Lugt, Stefan Nierkens, Marcel Kool, Eelco W. Hoving, Dennis S. Metselaar, Esther Hulleman
Abstract
Hormone Receptor positive (HR+) breast cancers (BC) are typically “immune-cold” poorly immune infiltrated tumors that do not respond to immune-checkpoint blockade (ICB) therapies. Using clinical data, we report that estrogen receptor (ERα) signaling associates with immunosuppressive pathways and lack of response to ICB in HR+ patients. In this study, we validate ER-mediated immunosuppression by engineering and modulating ER in preclinical models in vitro, in vivo and ex vivo. Mechanistically, we found that ERα hijacks LCOR, a nuclear receptor corepressor, thereby preventing LCOR’s function in the induction of tumor immunogenicity and immune infiltration, which is normally observed in the absence of ERα, such as in ER-negative BC. In HR+BC, we demonstrate that the molecular disruption of LCOR and ERα interaction using anti-ER therapies or using a mutant of the LCOR nuclear-receptor binding domain (LSKLL into LSKAA) that does not interact with ERα, restores LCOR’s immunogenic functions. Remarkably, the LCOR-ERα disruption converts HR+BC immune-cold tumors into immune-hot tumors responsive to ICB by increased antigen presentation machinery (APM) expression, immune infiltration, T cell recognition and mediated killing. In conclusion, ERα inhibition and the disruption of LCOR to ERα represent a novel therapeutic strategy and an opportunity to elicit immunotherapeutic benefit in HR+BC patients.
Authors
José Ángel Palomeque, Gabriel Serra-Mir, Sandra Blasco-Benito, Helena Brunel, Pau Torren-Duran, Iván Pérez-Núñez, Chiara Cannatá, Laura Comerma, Silvia Menendez, Sonia Servitja, Tamara Martos, Maria Castro, Rodrigo L. Borges, Joanna I. Lopez-Velazco, Sara Manzano, Santiago Duro-Sánchez, Joaquin Arribas, Maria M. Caffarel, Ander Urruticoechea, Jose A. Seoane, Lluis Morey, Joan Albanell, Toni Celià-Terrassa
Abstract
BACKGROUND. Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM. AIM. To identify biomarkers for prediction of CIADM. METHODS. From our prospective biobank, 14 CIADM patients who had metastatic melanoma treated with anti-PD-1 ± anti-CTLA4 were identified. Controls were selected from the same biobank, matched 2:1. Pre-treatment, on-ICI and post-CIADM serum and peripheral blood mononuclear cells (PBMCs) were analysed. Serum was analysed for T1D autoantibodies, C-peptide, glucose and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry. RESUTLS. Before treatment, CIADM patients had smaller pancreatic volume (27% reduction, p=0.044) and higher anti-GAD antibody titres (median 2.9 versus 0, p=0.01). They had significantly higher baseline proportions of Th17 helper cells (p=0.03), higher CD4+ central memory cells (p=0.04) and lower naïve CD4+ cells (p=0.01). With ICI treatment, greater declines in pancreatic volume were seen in CIADM patients (p<0.0001). Activated CD4+ subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAE) but not controls without IRAE. Using only pre-treatment results, pancreatic volume, anti-GAD antibody titre and baseline immune flow profile were highly predictive of CIADM development, with an area under the curve (AUC) of >0.96. CONCLUSIONS. People who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumours. FUNDING. JEG is supported by NHMRC Investigator grant 2033228. AMM by NHMRC Investigator grant 2009476 and GVL by NHMRC Investigator grant 2007839.
Authors
Linda Wu, John M. Wentworth, Christopher Liddle, Nicole Fewings, Matteo Carlino, David A. Brown, Roderick Clifton-Bligh, Georgina V. Long, Richard A. Scolyer, Nicholas Norris, Sarah C. Sasson, Venessa H.M. Tsang, Alexander M. Menzies, Jenny E. Gunton
Abstract
While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of cancer patients. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet the molecular mechanisms underlying impaired MHC-I remain to be fully elucidated. Herein, we identified USP22 as a critical factor responsible for ICB resistance through suppressing MHC-I-mediated neoantigen presentation to CD8 T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcome anti-PD-1 immunotherapeutic resistance. At the molecular level, USP22 functions as a deubiquitinase for the methyltransferase EZH2, leading to transcriptional silencing of MHC-I gene expression. Targeted Usp22 inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8 T cell killing, which was largely abrogated by Ezh2 reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both 2M expression and CD8+ T lymphocyte infiltration in solid tumors. Importantly, USP22 upregulation was associated with ICB immunotherapeutic resistance in patients with lung cancer. Collectively, this study highlights the role of USP22 as a diagnostic biomarker for ICB resistance and provides a potential therapeutic avenue to overcome the current ICB resistance through inhibition of USP22.
Authors
Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang
Abstract
N6-methyladenosine (m6A), the most predominant RNA modification in humans, participates in various fundamental and pathological bioprocesses. Dynamic manipulation of m6A deposition in the transcriptome is critical for cancer progression, while how this regulation is achieved remains understudied. Here, we report that in prostate cancer (PCa), Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) exerts an additional function in m6A regulation via its enzymatic activity. Mechanistically, EZH2 methylates and stabilizes FOXA1 proteins from degradation, which in turn facilitates the transcription of m6A reader YTHDF1. Through activating an m6A autoregulation pathway, YTHDF1 enhances the translation of METTL14 and WTAP, two critical components of the m6A methyltransferase complex (MTC), and thereby upregulates the global m6A level in PCa cells. We further demonstrate that inhibiting the catalytic activity of EZH2 suppresses the translation process globally through targeting the YTHDF1-m6A axis. By disrupting both the expression and interaction of key m6A MTC subunits, combinational treatment of EZH2 degrader MS8815 and m6A inhibitor STM2457 mitigates prostate tumor growth synergistically. Together, our study decodes a previously hidden interrelationship between EZH2 and mRNA modification, which may be leveraged to advance the EZH2-targeting curative strategies in cancer.
Authors
Yang Yi, Joshua Fry, Chaehyun Yum, Rui Wang, Siqi Wu, Sharath Narayan, Qi Liu, Xingxing Zhang, Htoo Zarni Oo, Ning Xie, Yanqiang Li, Xinlei Gao, Xufen Yu, Xiaoping Hu, Qiaqia Li, Kemal Keseroglu, Ertuğrul M. Özbudak, Sarki A. Abdulkadir, Kaifu Chen, Jian Jin, Jonathan C. Zhao, Xuesen Dong, Daniel Arango, Rendong Yang, Qi Cao
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)