Oncology
Abstract
Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.
Authors
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
Abstract
Radiotherapy triggers chemokine release and leukocyte infiltration in pre-clinical models through activation of the senescence-associated secretory phenotype (SASP). However, effects of irradiation on senescence and SASP in human tissue and in the context of particle radiotherapy remain unclear. Here, we analyzed chemokine patterns after radiotherapy of human pancreatic tumors and cancer cell lines. We show that irradiated tumor cells co-express SASP chemokines in defined modules. These chemokine modules correlated with infiltration of distinct leukocyte subtypes expressing cognate receptors. We developed a patient-derived pancreatic tumor explant system, which confirmed our identified radiation-induced chemokine modules. Chemokine modules were partially conserved in cancer cells in response to photon and particle irradiation showing a dose-dependent plateau effect and induced subsequent migration of NK and T cell populations. Hence, our work reveals redundant interactions of cancer cells and immune cells in human tissue, suggesting that targeting multiple chemokines is required to efficiently perturb leukocyte infiltration after photon or particle radiotherapy.
Authors
Joscha A. Kraske, Michael M. Allers, Aleksei Smirnov, Bénédicte Lenoir, Azaz Ahmed, Meggy Suarez-Carmona, Mareike Hampel, Damir Krunic, Alexandra Tietz-Dalfuß, Tizian Beikert, Jonathan M. Schneeweiss, Stephan Brons, Dorothee Albrecht, Thuy Trinh, Muzi Liu, Nathalia A. Giese, Christin Glowa, Jakob Liermann, Ramon Lopez Perez, Dirk Jäger, Jürgen Debus, Niels Halama, Peter E. Huber, Thomas Walle
Abstract
The tumor microenvironment (TME) significantly impacts cancer progression, yet traditional animal models do not fully recapitulate the situation in humans. To address this, we developed tumor-derived precision lung slices (TD-PCLS), an ex vivo platform for studying the lung TME and evaluating therapies. TD-PCLS, viable for 8 to 10 days, preserve the heterogeneity and metabolic activity of primary tumors, as confirmed by seahorse analysis. Using multispectral FACS and phenocycler multiplex imaging, we spatially profiled TME components and cancer cell functionality. Additionally, TD-PCLS revealed patient-specific responses to chemo- and immunotherapies. To complement TD-PCLS, we established tumor-cell-seeded PCLS (TCS-PCLS) by introducing tumor and immune cells into healthy lung slices. This model highlighted macrophage-tumor interactions as critical for tumor cell proliferation, migration, and immune modulation. Together, these platforms provide a robust tool for lung cancer research, enabling precision medicine and advancing therapeutic discovery.
Authors
Siavash Mansouri, Annika Karger, Clemens Ruppert, Marc A. Schneider, Andreas Weigert, Rajender Nandigama, Blerina Aliraj, Lisa Strotmann, Anoop V. Cherian, Diethard Pruefer, Peter Dorfmuller, Ludger Fink, Ibrahim Alkoudmani, Stefan Gattenlöhner, Bastian Eul, Andre Althoff, Peter Kleine, Hauke Winter, Andreas Guenther, Ardeschir Ghofrani, Soni S. Pullamsetti, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
Abstract
More than one third of patients with glioblastoma experience tumour progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier that to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumour recurrence in a mouse glioblastoma model, compared to treatment with TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.
Authors
Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das
Abstract
Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved anti-tumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.
Authors
Petra Wilgenbus, Jennifer Pott, Sven Pagel, Claudius Witzler, Jennifer Royce, Federico Marini, Sabine Reyda, Thati Madhusudhan, Thomas Kindler, Anne Hausen, Matthias M. Gaida, Hartmut Weiler, Wolfram Ruf, Claudine Graf
Abstract
RNA splicing factor SF3B1 is one of the most recurrently mutated genes in chronic lymphocytic leukemia (CLL) and frequently co-occurs with chromosome 13q deletion (del(13q)). This combination is associated with poor prognosis in CLL, suggesting these lesions increase CLL aggressiveness. While del(13q) in murine B cells (Mdr mice), but not expression of Sf3b1-K700E, drives the initiation of CLL, we hypothesize that SF3B1 mutation accelerates CLL progression. In this study, we crossed mice with a B-cell-specific Sf3b1-K700E allele with Mdr mice to determine the impact of Sf3b1 mutation on CLL progression. We found that the co-occurrence of these two lesions in murine B cells caused acceleration of CLL. We showed that Sf3b1-K700E impacted alternative RNA splicing of Nfatc1 and activated mTOR signaling and the MYC pathway, contributing to CLL acceleration. Moreover, concurrent inhibition of RNA splicing and mTOR pathways led to cell death in vitro and in vivo in murine CLL cells with SF3B1 mutation and del(13q). Our results thus suggest that SF3B1 mutation contributes to the aggressiveness of CLL by activating the mTOR pathway through alternative splicing of Nfatc1, providing a rationale for targeting mTOR and RNA splicing in the subset of CLL patients with both SF3B1 mutations and del(13q).
Authors
Bo Zhang, Prajish Iyer, Meiling Jin, Elisa ten Hacken, Zachary Cartun, Kevyn L. Hart, Mike Fernandez, Kristen Stevenson, Laura Rassenti, Emanuela M. Ghia, Thomas J. Kipps, Donna Neuberg, Ruben Carrasco, Wing Chan, Joo Y. Song, Yu Hu, Catherine Wu, Lili Wang
Abstract
Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in two mouse syngeneic models for colorectal cancer. Overexpressing the uracil DNA glycosylase inhibitor protein in mismatch repair (MMR)-deficient MC38 cells injected into C57/B6 mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared to FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared to FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into Balb/C mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG-depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune response in humans.
Authors
Eric S. Christenson, Brandon E. Smith, Thanh J. Nguyen, Alens Valentin, Soren Charmsaz, Nicole E Gross, Sarah M. Shin, Alexei Hernandez, Won Jin Ho, Srinivasan Yegnasubramanian, James T. Stivers
Abstract
Tumor immunosuppression impacts survival and treatment efficacy. Tumor NOS2/COX2 coexpression strongly predicts poor outcome in ER– breast cancer by promoting metastasis, drug resistance, cancer stemness, and immune suppression. Herein, a spatially distinct NOS2/COX2 and CD3+CD8+PD1– T effector (TEff) cell landscape correlated with poor survival in ER– tumors. NOS2 was primarily expressed at the tumor margin, whereas COX2 together with B7H4 was associated with immune desert regions lacking TEff cells, where a higher ratio of tumor NOS2 or COX2 to TEff cells predicted poor survival. Also, PDL1/PD1, regulatory T cells (TReg) and IDO1 were primarily associated with stroma restricted TEff cells. Regardless of the survival outcome, CD4+ T cells and macrophages were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to increased CD8+ TEff/CD4+ TReg ratio and CD8+ TEff infiltration while Nos2 deficiency had no significant effect, thus reinforcing our observations that COX2 is an essential component of immunosuppression through CD8+ TEff cell exclusion from the tumor. Our study indicates that tumor NOS2/COX2 expression plays a central role in tumor immune evasion, suggesting that strategies combining clinically available NOS2/COX2 inhibitors with immune therapy could provide effective options for the treatment of aggressive and drug-resistant ER– breast tumors.
Authors
Lisa A. Ridnour, Robert Y.S. Cheng, William F. Heinz, Milind Pore, Ana L. Gonzalez, Elise L. Femino, Rebecca L. Moffat, Adelaide L. Wink, Fatima Imtiaz, Leandro L. Coutinho, Donna Butcher, Elijah F. Edmondson, M. Cristina Rangel, Stephen T.C. Wong, Stanley Lipkowitz, Sharon A. Glynn, Michael P. Vitek, Daniel W. McVicar, Xiaoxian Li, Stephen K. Anderson, Nazareno Paolocci, Stephen M. Hewitt, Stefan Ambs, Timothy R. Billiar, Jenny C. Chang, Stephen J. Lockett, David A. Wink
Abstract
ADAR1 edits double-stranded RNAs (dsRNAs) by deaminating adenosines into inosines, preventing aberrant activation of innate immunity by endogenous dsRNAs, which may resemble viral structures. Several tumors exploit ADAR1 to evade immune surveillance; indeed, its deletion reduces tumor viability and reshapes infiltrating leukocytes. Here we investigated the role of ADAR1 in immune evasion mechanisms during cervical cancer (CC) progression. Patients’ biopsy samples showed higher ADAR1 expression already in premalignant lesions (squamous intraepithelial lesions [SIL]) and a substantially reduced percentage of infiltrating CD7+ innate cells in in situ and invasive carcinomas compared with normal mucosa, with CD56+ NK cells showing phenotypic alterations that may have affected their functional responses. In CC-derived cell lines (SiHa, CaSki), ADAR1 silencing reduced cell proliferation, an effect further enhanced by exogenous IFN-β administration. It also induced proinflammatory gene expression, as demonstrated by RNA-Seq analysis, and conditioned supernatants collected from these cells activated several NK cell effector functions. NK cell infiltration and activation were also confirmed in organotypic 3D tissue models of SiHa cells knocked out for ADAR1. In conclusion, ADAR1 expression increased with CC progression and was accompanied by alterations in tumor-infiltrating NK cells, but its silencing in CC-derived cell lines potentiated antitumor NK cell activities. Thus, ADAR1 inhibition may represent a therapeutic perspective for CC and possibly other malignancies.
Authors
Valentina Tassinari, Marta Kaciulis, Stefano Petrai, Helena Stabile, Angelina Pernazza, Martina Leopizzi, Valeria Di Maio, Francesca Belleudi, Danilo Ranieri, Vanessa Mancini, Innocenza Palaia, Federica Tanzi, Ludovica Lospinoso Severini, Silvia Ruggeri, Maria Emanuela Greco, Giovanni Bernardini, Alessandra Zingoni, Marco Cippitelli, Cristina Cerboni, Alessandra Soriani
Abstract
Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of GBM stem cells (GSCs) that interaction with surrounding cells, including infiltrating tumor-associated macrophages and microglia (TAMs). While GSCs and TAMs are in close proximity and likely interact to coordinate tumor growth, a limited number of mechanisms have been identified that support their communication. Here, we identified glycoprotein NMB (GPNMB) as a key factor mediating a unique bidirectional interaction between GSCs and TAMs in GBM. Specifically, GSCs educated macrophages and microglia to preferentially express GPNMB in the GBM tumor microenvironment. As a result, TAM-secreted GPNMB interacted with its receptor CD44 on GSCs to promote their glycolytic and self-renewal abilities via activating the PYK2/RSK2 signaling axis. Disrupting GPNMB-mediated GSC-TAM interplay suppressed tumor progression and self-renewal in GBM mouse models. Our study found a protumor function of GPNMB-mediated GSC-TAM bidirectional communication and supports GPNMB as a promising therapeutic target for GBM.
Authors
Yang Liu, Lizhi Pang, Fatima Khan, Junyan Wu, Fei Zhou, Craig Horbinski, Shideng Bao, Jennifer S. Yu, Justin D. Lathia, Peiwen Chen
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