Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalks among various cell compartments in supporting metastasis remain poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here we report an elevation of FGF-2 signaling in both nasopharyngeal carcinoma (NPC) patient samples and xenograft mouse models promotes NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1- AHR signaling. Gain and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization towards an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposomes treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2-FGFR1-pericyte-CXCL14-TAM stromal communication axis in NPC and propose an effective anti-metastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2-high tumors.
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway creating an urgent need for novel therapeutic targets. To unbiasedly find novel MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found protein arginine N-methyltransferase 5 (PRMT5) inhibitors to trigger a MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirm the increased efficacy of PRMT5 inhibitors in MYC deregulated PDACs. Although inhibition of PRMT5 is inducing DNA-damage and arresting PDAC cells in the G2/M-phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.
Felix Orben, Katharina Lankes, Christian Schneeweis, Zonera Hassan, Hannah Jakubowsky, Lukas Krauß, Fabio Boniolo, Carolin Schneider, Arlett P.G. Schäfer, Janine Murr, Christoph Schlag, Bo Kong, Rupert Öllinger, Chengdong Wang, Georg Beyer, Ujjwal Mukund Mahajan, Yonggan Xue, Julia Mayerle, Roland M. Schmid, Bernhard Kuster, Roland Rad, Christian J. Braun, Matthias Wirth, Maximilian Reichert, Dieter Saur, Günter Schneider
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.
Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel de la Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E. de Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M. Alonso
Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases, and its findings might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify non-small cell lung cancer (NSCLC) patients who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis were compared regarding therapeutic effect in 12 patients. Compared to ICI non-responders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and their balance could contribute to nivolumab sensitivity in NSCLC patients. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.
Kentaro Masuhiro, Motohiro Tamiya, Kosuke Fujimoto, Shohei Koyama, Yujiro Naito, Akio Osa, Takashi Hirai, Hidekazu Suzuki, Norio Okamoto, Takayuki Shiroyama, Kazumi Nishino, Yuichi Adachi, Takuro Nii, Yumi Kinugasa-Katayama, Akiko Kajihara, Takayoshi Morita, Seiya Imoto, Satoshi Uematsu, Takuma Irie, Daisuke Okuzaki, Taiki Aoshi, Yoshito Takeda, Toru Kumagai, Tomonori Hirashima, Atsushi Kumanogoh
Uveal melanoma (UM) represents a unique disease in that patients with primary UM are well stratified based on their risk of developing metastasis yet there are limited effective treatments once metastases occur. There is an urgent need to better understand the distinct molecular pathogenesis of UM and characteristics of patients at high risk for metastasis, to identify neo-antigenic targets which can be used in immunotherapy, and develop novel therapeutic strategies that may effectively target this lethal transition. An important and overlooked area of molecular pathogenesis and neoantigenic targets in UM come from human endogenous retroviruses (HERVs). We investigated the HERV expression landscape in primary UM and found that tumors stratified into four HERV-based subsets that provide clear delineation of risk outcome and support subtypes identified by other molecular indicators. Specific HERV loci are associated with the risk of uveal melanoma metastasis and may offer mechanistic insights into this process, including dysregulation of HERVs on chromosomes 3 and 8. A HERV signature comprised of 17 loci was sufficient to classify tumors according to subtype with >95% accuracy, including at least one intergenic HERV with coding potential (HERVE_Xp11.23) that could represent a new potential HERV E target for immunotherapy.
Matthew L. Bendall, Jasmine H. Francis, Alexander N. Shoushtari, Douglas F. Nixon
The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single-agent is not associated with anti-tumor activity in castration-resistant prostate cancer (CRPC) patients. We hypothesized that novel combinatorial strategies are likely to enhance the efficacy of BETi. Prior studies by our group and others have shown that BET proteins are essential for the repair of DNA double-strand breaks (DSBs) by the non-homologous end joining (NHEJ) as well as the homologous recombination (HR) DNA repair pathways. By using PCa patient‐derived explants (PDEs) and xenograft models, we show that BETi treatment enhances the efficacy of radiation therapy (RT) and also overcomes radioresistance. Mechanistically, BETi potentiates the activity of RT by blocking the repair of DNA DSBs. We also report a synthetic lethal relationship between BETi and Topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi, OTX015, synergizes with the new class of synthetic non-camptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiates the anti-tumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer (HSPC) to CRPC. Consistent with this observation, TOP1 was highly expressed in metastatic CRPC (mCRPC) and its expression correlated with the expression of BET family genes—BRD4, BRD3 and BRD2. These studies open new avenues for the rational combinatorial treatment of aggressive PCa—particularly, cancers refractory to androgen signaling inhibitors.
Xiangyi Li, GuemHee Baek, Suzanne Carreira, Wei Yuan, Shihong Ma, Mia Hofstad, Sora Lee, Yunpeng Gao, Claudia Bertan, Maria de los Dolores Fenor de la Maza, Prasanna G. Alluri, Sandeep Burma, Benjamin P.C. Chen, Ganesh V. Raj, Johann de Bono, Yves Pommier, Ram S. Mani
CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4–mediated CCNE1 upregulation compromises the G1/S transition to confer a dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator WEE1 as part of an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depended on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo led to rapid DNA damage–associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identified WEE1 as a vulnerability targetable by therapeutic intervention in CIC-DUX4 sarcomas.
Rovingaile Kriska M. Ponce, Nicholas J. Thomas, Nam Q. Bui, Tadashi Kondo, Ross A. Okimoto
Malignant pleural effusion (MPE) is an incurable common manifestation of many malignancies. Its formation is orchestrated by complex interactions among tumor cells, inflammatory cells, and the vasculature. Tumor-associated macrophages present the dominant inflammatory population of MPE, and M2 macrophage numbers account for dismal prognosis. M2 polarization is known to be triggered by CSF1/CSF1 receptor (CSF1R) signaling. We hypothesized that CSF1R+ M2 macrophages favor MPE formation and could be therapeutically targeted to limit MPE. We generated mice with CSF1R-deficient macrophages and induced lung and colon adenocarcinoma–associated MPE. We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma–induced experimental MPE. We showed that CSF1R+ macrophages promoted pleural fluid accumulation by enhancing vascular permeability, destabilizing tumor vessels, and favoring immune suppression. We also showed that CSF1R inhibition limited MPE in vivo by reducing vascular permeability and neoangiogenesis and impeding tumor progression. This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE.
Chrysavgi N. Kosti, Photene C. Vaitsi, Apostolos G. Pappas, Marianthi P. Iliopoulou, Katherina K. Psarra, Sophia F. Magkouta, Ioannis T. Kalomenidis
INTRODUCTION. Immune cell profiling of primary and metastatic central nervous system (CNS) tumors has been focused on the tumor, not the tumor microenvironment (TME), or have been analyzed via biopsies. METHODS. En bloc resections of glioma (n=10) and lung metastasis (n=10) underwent tissue segmentation and high dimension opal 7-color multiplex imaging. Single cell RNA analyses inferred immune cell functionality. RESULTS. Within gliomas, T cells were localized to the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes, were commonly observed. In lung metastases, T cells interact with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself, and as clusters within the necrotic core. In contrast, gliomas typically lack dyad and cluster interactions, except for T cell-CD68+cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells express both pro-inflammatory and immune suppressive gene signatures. CONCLUSION. Our results show that immunosuppressive macrophages are abundant within the TME, and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.
Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M. Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N. Krishnan, Frederick S. Varn, Víctor A. Arrieta, Pravesh Gupta, Sherise D. Ferguson, Jason T. Huse, Gregory N. Fuller, James P. Long, Daniel E. Winkowski, Benjamin A. Freiberg, C. David James, Leonidas C. Platanias, Maciej S. Lesniak, Jared K. Burks, Amy B. Heimberger
Therapeutic IL-12 has demonstrated the ability to reduce local immune suppression in preclinical models, but clinical development has been limited by severe inflammation-related adverse events with systemic administration. Here, we show that potent immunologic tumor control of established syngeneic carcinomas can be achieved by i.t. administration of a tumor-targeted IL-12 antibody fusion protein (NHS–rmIL-12) using sufficiently low doses to avoid systemic toxicity. Single-cell transcriptomic analysis and ex vivo functional assays of NHS–rmIL-12–treated tumors revealed reinvigoration and enhanced proliferation of exhausted CD8+ T lymphocytes, induction of Th1 immunity, and a decrease in Treg number and suppressive capacity. Similarly, myeloid cells transitioned toward inflammatory phenotypes and displayed reduced suppressive capacity. Cell type–specific IL-12 receptor–KO BM chimera studies revealed that therapeutic modulation of both lymphoid and myeloid cells is required for maximum treatment effect and tumor cure. Study of single-cell data sets from human head and neck carcinomas revealed IL-12 receptor expression patterns similar to those observed in murine tumors. These results describing the diverse mechanisms underlying tumor-directed IL-12–induced antitumor immunity provide the preclinical rationale for the clinical study of i.t. NHS–IL-12.
Youji Hong, Yvette Robbins, Xinping Yang, Wojciech K. Mydlarz, Anastasia Sowers, James B. Mitchell, James L. Gulley, Jeffrey Schlom, Sofia R. Gameiro, Cem Sievers, Clint T. Allen
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