Oncologies
Abstract
Bone metastases are a common complication of breast cancer. We have demonstrated that intermittent administration of parathyroid hormone (PTH [1-34]) reduces the incidence of bone metastases in murine models of breast cancer by acting on osteoblasts to alter the bone microenvironment. Here, we examined the role of PTH receptor (PTH1R)-mediated signaling in both osteoblasts and breast cancer cells in influencing bone metastases. In mice with impaired PTH1R signaling in osteoblasts, intermittent PTH did not reduce bone metastasis. Intermittent PTH also failed to reduce bone metastasis when expression of PTH1R was knocked down in 4T1 murine breast cancer cells by shRNA. In 4T1 breast cancer cells, PTH decreased expression of PTH-related protein (PTHrP), implicated in the vicious cycle of bone metastases. Knockdown of PTHrP in 4T1 cells significantly reduced migration towards MC3T3-E1 osteoblasts, and migration was further inhibited by treatment with intermittent PTH. Conversely, overexpression of PTHrP in 4T1 cells increased migration towards MC3T3-E1 osteoblasts and this was not inhibited by PTH. In conclusion, PTH1R expression is crucial in both osteoblasts and breast cancer cells for PTH to reduce bone metastases and in breast cancer cells this may be mediated in part by suppression of PTHrP.
Authors
Srilatha Swami, Hui Zhu, Aria Nisco, Takaharu Kimura, Matthew J. Kim, Vaisakh Nair, Joy Y. Wu
Abstract
BACKGROUND. Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin lymphoma (T-NHL), but some T-NHL patients have experienced hyperprogression with undetermined mechanisms upon anti-PD-1 therapy. METHODS. Single-cell RNA sequencing, whole-genome sequencing, whole-exome sequencing, and functional assays were performed on primary malignant T cells from a patient with advanced cutaneous T cell lymphoma, who experienced hyperprogression upon anti-PD-1 treatment. RESULTS. The patient was enrolled in a clinical trial of anti-PD-1 therapy and experienced disease hyperprogression. Single-cell RNA sequencing revealed that PD-1 blockade elicited a remarkable activation and proliferation of the CD4+ malignant T cells, which showed functional PD-1 expression and an exhausted status. Further analyses identified somatic amplification of PRKCQ in the malignant T cells. PRKCQ encodes PKCθ, a key player in the T cell activation/NF-kB pathway. PRKCQ amplification led to high expressions of PKCθ and p-PKCθ (T538) on the malignant T cells, resulting in an oncogenic activation of the T cell receptor (TCR) signaling pathway. PD-1 blockade in this patient released this signaling, de-repressed the proliferation of malignant T cells, and resulted in disease hyperprogression. CONCLUSIONS. Our study provides real-world clinical evidence that PD-1 acts as a tumor suppressor for malignant T cells with oncogenic TCR activation. TRIAL REGISTRATION. ClinicalTrials.gov (NCT03809767). FUNDING. The National Natural Science Foundation of China (81922058), the National Science Fund for Distinguished Young Scholars (T2125002), the National Science and Technology Major Project (2019YFC1315702), the National Youth Top-Notch Talent Support Program (283812), and the Peking University Clinical Medicine plus X Youth Project (PKU2019LCXQ012).
Authors
Yumei Gao, Simeng Hu, Ruoyan Li, Shanzhao Jin, Fengjie Liu, Xiangjun Liu, Yingyi Li, Yicen Yan, Weiping Liu, Jifang Gong, Shuxia Yang, Ping Tu, Lin Shen, Fan Bai, Yang Wang
Abstract
CD4+ T cells play a critical role in anti-tumor immunity via recognition of peptide antigens presented on MHC class II (MHC-II). Although some solid cancers can be induced to express MHC-II, the extent to which this enables direct recognition by tumor-specific CD4+ T cells is unclear. We isolated and characterized T cell antigen receptors (TCRs) from naturally primed CD4+ T cells specific for two oncoproteins, HPV16 E6 and the activating KRASG12V mutation, from head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) patients, respectively, and determined their ability to recognize autologous or human leukocyte antigen (HLA)-matched antigen-expressing tumor cells. We find in both cases that the TCRs are capable of recognizing peptide-loaded target cells expressing the relevant MHC-II or B cell antigen-presenting cells (APC) when the antigens are endogenously expressed and directed to the endosomal pathway but fail to recognize tumor cells expressing the source protein even after induction of surface MHC-II expression by IFN- or transduction with CIITA. These results suggest that priming and functional recognition of both a nuclear (E6) and a membrane-associated (KRAS) oncoprotein is predominantly confined to cross-presenting APC rather than via direct recognition of tumor cells induced to express MHC-II.
Authors
Spencer E. Brightman, Martin S. Naradikian, Rukman R. Thota, Angelica Becker, Leslie Montero, Milad Bahmanof, Ashmitaa Premlal, Jason A. Greenbaum, Bjoern Peters, Ezra E.W. Cohen, Aaron M. Miller, Stephen P. Schoenberger
Abstract
BACKGROUND. Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Its value in hematologic malignancy remains to be explored, in particular in adult patients. METHODS. We performed chronotherapeutic analysis using two cohorts of diffuse large B cell lymphoma (DLBCL) patients undergoing chemotherapy with a dichotomized schedule (morning or afternoon). The effect of a morning or afternoon schedule of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on survival and drug tolerability were evaluated in a survival cohort (n = 210) and an adverse event cohort (n = 129), respectively. Analysis of ~14,000 healthy subjects was followed to identify the circadian variation in hematologic parameters. RESULTS. Both progression-free survival (PFS) and overall survival (OS) of female, but not male, patients were significantly shorter when patients received chemotherapy mostly in the morning (PFS hazard ratio [HR] 0.357; P = 0.033 and OS HR 0.141; P = 0.032). The dose intensity was reduced in female patients treated in the morning (cyclophosphamide 10%; P = 0.002, doxorubicin 8%; P = 0.002 and rituximab 7%; P = 0.003). This was mainly attributable to infection and neutropenic fever: female patients treated in the morning suffered from a higher incidence of infections (16.7% vs 2.4%) and febrile neutropenia (20.8% vs 9.8%) as compared to those treated in the afternoon. The sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in females than in males. CONCLUSIONS. In female DLBCL patients, R-CHOP treatment in the afternoon can reduce the toxicity while it improves the efficacy and the survival outcome.
Authors
Dae Wook Kim, Ja Min Byun, Jeong-Ok Lee, Jae Kyoung Kim, Youngil Koh
Abstract
Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1–/–, Phd2+/–, Phd3–/–, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1–/– mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3–/– mice, colitis activity and CAC growth remained unaltered. In Phd2+/– mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal–regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.
Authors
Kilian B. Kennel, Julius Burmeister, Praveen Radhakrishnan, Nathalia A. Giese, Thomas Giese, Martin Salfenmoser, Jasper M. Gebhardt, Moritz J. Strowitzki, Cormac T. Taylor, Ben Wielockx, Martin Schneider, Jonathan M. Harnoss
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%–40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODS We performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTS In human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSION Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDING This work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.
Authors
Max Heiduk, Ioana Plesca, Jessica Glück, Luise Müller, David Digomann, Charlotte Reiche, Janusz von Renesse, Rahel Decker, Christoph Kahlert, Ulrich Sommer, Daniela E. Aust, Marc Schmitz, Jürgen Weitz, Lena Seifert, Adrian M. Seifert
Abstract
Despite advances in ovarian cancer (OC) therapy, recurrent OC remains a poor-prognosis disease. Because of the close interaction between OC cells and the tumor microenvironment (TME), it is important to develop strategies that target tumor cells and engage components of the TME. A major obstacle in the development of OC therapies is the identification of targets with expression limited to tumor surface to avoid off-target interactions. The follicle-stimulating hormone receptor (FSHR) has selective expression on ovarian granulosa cells and is expressed on 50%–70% of serous OCs. We generated mAbs targeting the external domain of FSHR using in vivo–expressed FSHR vector. By high-throughput flow analysis, we identified multiple clones and downselected D2AP11, a potent FSHR surface–targeted mAb. D2AP11 identifies important OC cell lines derived from tumors with different mutations, including BRCA1/2, and lines resistant to a wide range of therapies. We used D2AP11 to develop a bispecific T cell engager. In vitro addition of PBMCs and T cells to D2AP11-TCE induced specific and potent killing of different genetic and immune escape OC lines, with EC50s in the ng/ml range, and attenuated tumor burden in OC-challenged mouse models. These studies demonstrate the potential utility of biologics targeting FSHR for OC and perhaps other FSHR-positive cancers.
Authors
Devivasha Bordoloi, Pratik S. Bhojnagarwala, Alfredo Perales-Puchalt, Abhijeet J. Kulkarni, Xizhou Zhu, Kevin Liaw, Ryan P. O’Connell, Daniel H. Park, Daniel W. Kulp, Rugang Zhang, David B. Weiner
Abstract
The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology–based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule–based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC — especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.
Authors
Jinmei Jin, Yaping Wu, Zeng Zhao, Ye Wu, Yu-dong Zhou, Sanhong Liu, Qingyan Sun, Guizhu Yang, Jiayi Lin, Dale G. Nagle, Jiangjiang Qin, Zhiyuan Zhang, Hong-zhuan Chen, Weidong Zhang, Shuyang Sun, Xin Luan
Abstract
Metastatic clear cell renal cell carcinomas (ccRCC) are resistant to DNA damaging chemotherapies, limiting therapeutic options for patients whose tumours are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCC are frequently characterised by high levels of endogenous DNA damage and that cultured ccRCC cells exhibit intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage sensing kinase ATR with the orally administered, potent and selective drug M4344 (also called gartisertib) induces anti-proliferative effects in ccRCC cells due to replication stress and the accumulation of DNA damage in S phase. In some cells, DNA damage persists into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single agent treatment with M4344 inhibited the growth of ccRCC xenograft tumours. M4344 synergises with chemotherapeutic drugs including cisplatin and carboplatin and the PARP inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed in vivo therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.
Authors
Philipp Seidel, Anne Rubarth, Kyra Zodel, Asin Peighambari, Felix Neumann, Yannick Federkiel, Hsin Huang, Rouven Hoefflin, Mojca Adlesic, Christian Witt, David J. Hoffmann, Patrick Metzger, Ralph K. Lindemann, Frank T. Zenke, Christoph Schell, Melanie Boerries, Dominik von Elverfeldt, Wilfried Reichardt, Marie Follo, Joachim Albers, Ian J. Frew
Abstract
Chronic inflammation is associated with lung tumorigenesis, in which NF-κB-mediated epigenetic regulations play a critical role. Lung tumor suppressor GPRC5A is repressed in most non-small cell lung cancer (NSCLC), however the mechanisms remain unclear. Here, we show that NF-κB acts as a transcriptional repressor in suppression of GPRC5A. NF-κB induces GPRC5A repression both in vitro and in vivo. Intriguingly, trans-activation of NF-κB downstream targets is not required, but the trans-activation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in GPRC5A promoter. Instead, p65 was complexed with RARα/β, and recruited to the RA-response element (RARE) site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complex, and suppressed transcription. Noticeably, phosphorylation on Serine276 of p65 is required for interaction with RARα/β and repression of GPRC5A. Moreover, NF-κB-mediated epigenetic repression is through suppression of histone H3K9ac, but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a HDAC inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via complex with RARα/β and mediates epigenetic repression via suppression of H3K9ac.
Authors
Hongyong Song, Xiaofeng Ye, Yueling Liao, Siwei Zhang, Dongliang Xu, Shuangshuang Zhong, Bo Jing, Tong Wang, Beibei Sun, Jianhua Xu, Wenzheng Guo, Kaimi Li, Min Hu, Yanbin Kuang, Jing Ling, Tuo Zhang, Yadi Wu, Jing Du, Feng Yao, Yugene Chin, Qi Wang, Binhua P. Zhou, Jiong Deng
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