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Redmond WL. Challenges and opportunities in the development of combination immunotherapy with OX40 agonists. Expert Opin Biol Ther 2023; 23:901-912. [PMID: 37587644 PMCID: PMC10530613 DOI: 10.1080/14712598.2023.2249396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 08/18/2023]
Abstract
INTRODUCTION Costimulatory members of the tumor necrosis factor receptor family, such as OX40 (CD134), provide essential survival and differentiation signals that enhance T cell function. Specifically, OX40 (CD134) agonists stimulate potent anti-tumor immunity in a variety of preclinical models but their therapeutic impact in patients with advanced malignancies has been limited thus far. AREAS COVERED In this review, we discuss the current state of combination immunotherapy with OX40 agonists including preclinical studies and recent clinical trials. We also discuss the strengths and limitations of these approaches and provide insight into alternatives that may help enhance the efficacy of combination OX40 agonist immunotherapy. EXPERT OPINION OX40 agonist immunotherapy has not yet demonstrated significant clinical activity as a monotherapy or in combination with immune checkpoint blockade (ICB), likely due to several factors including the timing of administration, drug potency, and selection of agents for combination therapy clinical trials. We believe that careful consideration of the biological mechanisms regulating OX40 expression and function may help inform new approaches, particularly in combination with novel agents, capable of increasing the therapeutic efficacy of this approach.
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Affiliation(s)
- William L Redmond
- Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan St., 2N35, Portland, OR, 97213
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Corapi E, Carrizo G, Compagno D, Laderach D. Endogenous Galectin-1 in T Lymphocytes Regulates Anti-prostate Cancer Immunity. Front Immunol 2018; 9:2190. [PMID: 30319642 PMCID: PMC6169479 DOI: 10.3389/fimmu.2018.02190] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 09/04/2018] [Indexed: 12/20/2022] Open
Abstract
The identification of effective new therapies for prostate cancer (PCa) requires a better understanding of the multiple molecular interactions between tumor cells and their associated microenvironment. In this context, galectin-1 (Gal-1) is a key molecule in the determination of the prostatic carcinoma microenviroment; therefore, it is essential to understand all the molecular processes in which this protein is involved. Most of the previous studies found in the literature have focused on the microenvironment remodeling properties of tumor-secreted Gal-1, through its interactions with the glyco-receptors at the cell membrane and the extracellular matrix. This report shows original aspects of the lectin by focusing on the role of lymphocyte endogenous Gal-1 in controlling anti-prostate tumor immunity. Using a murine preclinical model of prostate cancer, our results demonstrate that endogenous Gal-1 in lymphocytes modulates their proliferative rate and cytotoxic function in conditions of high extracellular Gal-1 concentration, mainly derived from tumor cells. In such conditions, the absence of Gal-1 in T lymphocytes potentiates anti-tumor immune responses. Further studies demonstrated that endogenous Gal-1 in CD4+, but mainly in CD8+T cells, acts as a negative regulator of anti-tumor immunity. In conclusion, prostate tumors require Gal-1 in lymphocytes to evade immune responses. This report lays the foundation for an original immunotherapy strategy for prostate cancer.
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Affiliation(s)
- Enrique Corapi
- Laboratorio de Glico-Oncología Molecular y Funcional, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.,CONICET-Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Gustavo Carrizo
- Laboratorio de Glico-Oncología Molecular y Funcional, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.,CONICET-Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Daniel Compagno
- Laboratorio de Glico-Oncología Molecular y Funcional, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.,CONICET-Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Diego Laderach
- Laboratorio de Glico-Oncología Molecular y Funcional, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.,CONICET-Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.,Departamento de Ciencias Básicas, Universidad Nacional de Luján, Buenos Aires, Argentina
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Intracellular galectin-7 expression in cancer cells results from an autocrine transcriptional mechanism and endocytosis of extracellular galectin-7. PLoS One 2017; 12:e0187194. [PMID: 29117220 PMCID: PMC5678874 DOI: 10.1371/journal.pone.0187194] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 10/16/2017] [Indexed: 11/19/2022] Open
Abstract
The β-galactoside binding protein galectin-7 (gal-7) is constitutively expressed at abnormally high levels in the outside milieu and intracellular compartments of many types of epithelial cancer cells, most notably in aggressive forms of ovarian and breast cancer. It is thus of utmost importance to understand how gal-7 traffics between both intracellular and extracellular compartments to develop novel drugs that target the protumorigenic functions of galectin-7. In the present work, we report that extracellular gal-7 plays a central role in controlling intracellular gal-7 in cells. It does so via two distinct yet complementary mechanisms: firstly by increasing the transcriptional activation of lgals7 gene transcription, and secondly via re-entry into the cells. Increased mRNA levels were dose- and time-dependent and occur in all cell lines tested, including ovarian and breast cancer cell lines. Addition of recombinant gal-7 to MDA-MB-231 transfected with a luciferase reporter vector containing response elements of the lgals7 promoter indicated that increased mRNA level of lgals7 occurs via de novo gene transcription. Re-entry of extracellular gal-7 inside cells was rapid, and reached cytosolic and mitochondrial compartments. Taken together, these findings reveal the existence of a positive self-amplification pathway that regulates intracellular gal-7 expression in breast and ovarian cancer cells.
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Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers. Sci Rep 2017; 7:13244. [PMID: 29038585 PMCID: PMC5643335 DOI: 10.1038/s41598-017-13802-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 10/02/2017] [Indexed: 12/25/2022] Open
Abstract
Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independent predictors of chemoresistance and overall survival (OS), respectively. This galectin signature increased the predictive value of the cancer antigen 125 (CA125) on 5-year disease-free survival (DFS), post-chemotherapy treatment and 5-year OS. In CA125LOW patients, epithelial gal-9 was associated with a lower 5-year OS while stromal gal-1 and epithelial gal-8 were both associated with a lower 5-year DFS. Such negative predictive value of gal-8 and gal-9 was also found using plasma samples. In both cases, high plasma levels of gal-8 and gal-9 was associated with a lower OS and DFS. Overall, these data suggest that galectins may be promising biomarkers to identify subgroups of HGSC patients with poorer prognosis. Our study also contributes to better define the heterogeneity of the disease.
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Bacigalupo ML, Carabias P, Troncoso MF. Contribution of galectin-1, a glycan-binding protein, to gastrointestinal tumor progression. World J Gastroenterol 2017; 23:5266-5281. [PMID: 28839427 PMCID: PMC5550776 DOI: 10.3748/wjg.v23.i29.5266] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 05/04/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.
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Martínez-Bosch N, Fernández-Barrena MG, Moreno M, Ortiz-Zapater E, Munné-Collado J, Iglesias M, André S, Gabius HJ, Hwang RF, Poirier F, Navas C, Guerra C, Fernández-Zapico ME, Navarro P. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. Cancer Res 2014; 74:3512-24. [PMID: 24812270 PMCID: PMC4332591 DOI: 10.1158/0008-5472.can-13-3013] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy.
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Affiliation(s)
| | - Maite G Fernández-Barrena
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
| | | | | | - Jessica Munné-Collado
- Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona
| | - Mar Iglesias
- Authors' Affiliations: Cancer Research Program and Department of Pathology, IMIM (Hospital del Mar Medical Research Institute), Barcelona
| | - Sabine André
- Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and
| | - Hans-Joachim Gabius
- Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, München, Germany; and
| | - Rosa F Hwang
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Françoise Poirier
- Institute Jacques Monod, CNRS UMR7592, Université Paris Diderot, Paris, France
| | | | | | - Martin E Fernández-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota
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Compagno D, Gentilini LD, Jaworski FM, Pérez IG, Contrufo G, Laderach DJ. Glycans and galectins in prostate cancer biology, angiogenesis and metastasis. Glycobiology 2014; 24:899-906. [PMID: 24939371 DOI: 10.1093/glycob/cwu055] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, among other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.
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Affiliation(s)
- Daniel Compagno
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Lucas D Gentilini
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Felipe M Jaworski
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ignacio González Pérez
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Geraldine Contrufo
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego J Laderach
- Structural and Functional Glycomics Laboratory, IQUIBICEN-CONICET, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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Bacigalupo ML, Manzi M, Rabinovich GA, Troncoso MF. Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma. World J Gastroenterol 2013; 19:8831-8849. [PMID: 24379606 PMCID: PMC3870534 DOI: 10.3748/wjg.v19.i47.8831] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 11/02/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. Infections with hepatitis B or C virus, non-alcoholic steatohepatitis disease, alcohol abuse, or dietary exposure to aflatoxin are the major risk factors to the development of this tumor. Regardless of the carcinogenic insult, HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis. Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity for β-galactosides and conserved sequence motifs. Here, we summarize the current literature implicating galectins in the pathogenesis of HCC. Expression of "proto-type" galectin-1, "chimera-type" galectin-3 and "tandem repeat-type" galectin-4 is up-regulated in HCC cells compared to their normal counterparts. On the other hand, the "tandem-repeat-type" lectins galectin-8 and galectin-9 are down-regulated in tumor hepatocytes. The abnormal expression of these galectins correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, postoperative recurrence and poor prognosis. Moreover, these galectins have important roles in other pathological conditions of the liver, where chronic inflammation and/or fibrosis take place. Galectin-based therapies have been proposed to attenuate liver pathologies. Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.
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Galectins as new prognostic markers and potential therapeutic targets for advanced prostate cancers. Prostate Cancer 2013; 2013:519436. [PMID: 24205440 PMCID: PMC3800608 DOI: 10.1155/2013/519436] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 08/06/2013] [Accepted: 08/08/2013] [Indexed: 12/21/2022] Open
Abstract
A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the “galectin-signature” might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa.
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