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M cells and the follicle-associated epithelium
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Hiroshi Ohno, Marian Neutra, Ifor R. Williams
M cells display distinct proteins on their basolateral membrane to attract lymphocytes into the intraepithelial pocket. For example, M cells express on their basolateral membranes a membrane-bound form of the chemokine CXCL16, a molecule that interacts with CXCR6 on T and B cells. M cells also express CD137, an integrin family member that is recognized by certain B cells. Mice deficient in CD137 have Peyer's patches, FAE, and M cells with typical apical markers, but their M cells fail to form pockets and do not harbor intraepithelial lymphocytes.
Multi-scale modeling approaches: application in chemo– and immuno–therapies
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Modulating the interplay between the immune system and cancer cells via immunotherapy alone or on in combination with other therapeutics is becoming one of the most promising cancer treatment approaches. Due to the complexity of this interplay, computational modeling methods are playing a pivotal role [463]. A summary of such efforts using different modeling approaches is shown in Figure 11.9 [485]. For instance, an agent-based (cf. Section 11.3.2) model was used to study the effects of a specific immunotherapy strategy against B16-melanoma cell lines in mice and to predict the role of CD137 (tumor necrosis factor (TNF) receptor family) expression on tumor vessel endothelium for successful therapy [486]. Another study applied a discrete-time pharmacodynamic model to illustrate the potential synergism between immune checkpoint inhibitors (PD1-PDL1 axis and/or the CTLA-4) and radiotherapy. The effects of irradiation were described by a modified version of the linear-quadratic (LQ) model [487]. The model was able to explain the biphasic relationship between the size of a tumor and its immunogenicity, as measured by the abscopal effect, i.e., an induced non-localized immune response. Moreover, it explained why discontinuing immunotherapy may result in either tumor recurrence or a durably sustained response indicating potential for better synergistic scheduling [487].
Immunotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
Another group of receptors with a manipulating effect on immune cells includes other checkpoint receptors such as LAG-3 or the killer-cell immunoglobulin-like receptors (KIRs) (Campbell and Purdy 2011). They regulate immune response by interaction with MHC I molecules. Most of the receptors inhibit cytotoxicity, mostly by turning off NK cells when HLA is exhibited on tumor cells. Current ongoing trials are testing an anti-KIR moAb in conjugation with ipilimumab (NCT01750580) or nivolumab (NCT01714739). Anti-PD1 monoclonal antibodies were also being examined in various novel combinations in a phase I setting, such as nivolumab plus agonistic anti-CD137 moAbs (urelumab, NCT02253992), nivolumab plus anti-LAG-3 (NCT01968109), and cetuximab plus urelumab.
Synergistic antitumor response with recombinant modified virus Ankara armed with CD40L and CD137L against peritoneal carcinomatosis
Published in OncoImmunology, 2022
Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, Assunta Cirella, Myriam Fernandez-Sendin, Celia Gomar, Joan Salvador Russo-Cabrera, Inmaculada Rodríguez, José González-Gomariz, Maite Alvarez, Álvaro Teijeira, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda
Recently, the expression of CD40 ligand or CD137 ligand with tumor-associated antigens by MVA vectors has been shown to enhance the antitumor efficacy of these vectors dramatically.13,14 CD40 plays a critical role in the activation of dendritic cells. Ligation of CD40 on the professional antigen-presenting cells triggers the production of IL-12 and licenses them for CD8+ T lymphocyte priming.15,16 CD137 is expressed in activated T lymphocytes, and its ligation promotes survival, expansion, and effector functions of activated T cells.17,18 Thus, CD40 and CD137 are potent immunostimulatory molecules with complementary mechanisms of action. The potential of combining both co-stimulatory pathways has been previously demonstrated in preclinical cancer models.19
Combination of HER2-targeted agents with immune checkpoint inhibitors in the treatment of HER2-positive breast cancer
Published in Expert Opinion on Biological Therapy, 2022
Ashley Matusz-Fisher, Antoinette R. Tan
Novel combination strategies are being explored with avelumab to optimize antigen presentation. One example is the randomized phase II AVIATOR TBCRC045 (NCT03414658) trial evaluating avelumab in combination with trastuzumab, vinorelbine and utomilumab (PF-05082566), a human IgG2 monoclonal antibody that binds to the extracellular domain of CD137 agonist (Table 2). CD137 is expressed on activated T cells and natural killer (NK) cells. There is up-regulation of CD137 expression on NK cells by trastuzumab, as well as stimulation of NK function by CD137 agonists. Preclinical studies show that combining trastuzumab and a CD137 agonist is synergistic [48]. An estimated 100 patients unselected for PD-L1 will be randomized to one of three groups. The comparator arm will receive trastuzumab and vinorelbine, experimental arm 1 will receive trastuzumab, vinorelbine and avelumab, and experimental arm 2 will receive trastuzumab, vinorelbine, avelumab and utomilumab. There is a crossover arm available for patients in the comparator arm. The crossover arm treatment regimen is trastuzumab, atezolizumab and utomilumab. Eligible HER2-positive metastatic breast cancer patients must have received prior trastuzumab, pertuzumab and T-DM1. The primary endpoint is PFS.
Ectopic CD137 expression by rhabdomyosarcoma provides selection advantages but allows immunotherapeutic targeting
Published in OncoImmunology, 2021
Kang Yi Lee, Hiu Yi Wong, Qun Zeng, Jia Le Lin, Man Si Cheng, Chik Hong Kuick, Kenneth Tou En Chang, Amos Hong Pheng Loh, Herbert Schwarz
Under physiological conditions, CD137 is expressed by leukocytes and vascular endothelial cells. However, CD137 expression can be induced ectopically on nonimmune cells and malignant cells. Epstein Barr virus-encoded latent membrane protein-1 (LMP-1) induces CD137 expression on HRS cells in HL via the PI3K-AKT-mTOR pathway.41,42 Similarly, the human T-lymphotropic virus-1 protein tax induces CD137 on NK/T cell lymphomas.43 Since RMS cells originate from mesenchymal myogenic progenitors with no known association to oncogenic viruses, we hypothesized that molecules in the tumor microenvironment may induce the ectopic CD137 expression. A prime candidate is TNF since CD137 is expressed by blood vessel walls in inflammatory tissues and in tumors, and is induced on vascular endothelial cells by TNF.34,36