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Lymphocyte homing and immunology of extranodal lymphoid tissues
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Mariagrazia Uguccioni, James J Campbell, Katrin Kuscher, Marshall E Kadin
PTCL-U is a heterogeneous group of tumors. Patients present with nodal involvement but often have infiltrates of extranodal tissues such as bone marrow, liver, spleen, and skin. Japanese investigators attempted to understand patterns of organ involvement by analysis of chemokine receptors. They assigned distinct patterns of chemokine receptors and activated T-cell receptor OX40/CD134 to AILD and ALCL.87 Nearly all cases of AILD expressed OX40/CD134 (96%) and Th1-associated CXCR3. In contrast, ALCL cases were negative for OX40/CD134 and only infrequently positive for CXCR3 (24%) but positive for Th2-associated ST2(L) in 94% of cases. Cases of PTCL-U, were divided into two groups: group 1 (cases positive for either ST2(L), CCR5, or CXCR3) tended to show a favorable prognosis compared with group 2 (cases negative for ST2(L), CCR5, and CXCR3). Ishida et al found CCR4 to be a significant unfavorable prognostic marker in PTCL-U.83 They found a significant correlation between mRNA expression of CCR4 and Foxp3, suggesting an association with the immunocompromised states of these patients.
Cardiovascular Complications of Immune Checkpoint Inhibitors
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Sultan Tousif, Anand Prakash Singh, Prachi Umbarkar, Hind Lal
The co-stimulatory signal, which regulates the recognition of antigens by the TCR, can also be termed as an immune checkpoint. Immune checkpoints can be either costimulatory or co-inhibitory. CD27, CD37, CD40, GITR (CD278), and OX40 (CD134) are co-stimulatory immune checkpoints that fall under the tumor necrosis factor (TNF) superfamily, whereas CD28 and ICOS stimulatory signals belong to the B7-CD28 superfamily. Programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), adenosine A2A receptor (A2AR), indoleamine 2,3-dioxygenase (IDO), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform 2 (NOX-2), and V-domain Ig suppressor of T cell activation (VISTA) are considered as co-inhibitory immune checkpoints. On exposure to pathogens, adaptive immune cells are activated by antigen presentation and the signals induced by co-stimulatory immune checkpoints to protect the healthy tissues from damage [1]. The inhibitory immune checkpoint competes with the co-stimulatory molecule to diminish host immunity during pathogenic attacks, cancer, or other deadly diseases that hijack the host immune system [2]. This concerted action of co-stimula-tory and inhibitory signals ensures that the immune system does not keep firing once the offending pathogen or disease stimulus has been neutralized. Pathogens and cancer cells have devised smart ways to exploit such inhibitory immune checkpoints to evade host immune response [3, 4]. Therefore, immune checkpoint therapy relies on reactivation of immune function by using either an agonist of the co-stimulatory signal or an antagonist of inhibitory immune checkpoint molecules [5].
OX40 agonists for cancer treatment: a patent review
Published in Expert Opinion on Therapeutic Patents, 2021
Jorge Cebada, Martin Perez-Santos, Cindy Bandala, Eleazar Lara-Padilla, Irma Herrera-Camacho, Nora Hilda Rosas-Murrieta, Lourdes Millán-Pérez Peña, Eduardo Monjaraz, Amira Flores, Maricruz Anaya-Ruiz
OX40, also known as CD134 or TNFRS44 is a membrane protein expressed in CD4+ and CD8 + T cells, as well as neutrophils and NK cells, that performs co-stimulatory functions, through binding to its ligand, OX40L, during T cell activation [14,15]. Through various signaling pathways, e.g. NF-κB pathway, OX40 causes a high production of cytokines and the generation of memory and effector T cells Figure 1 [16–18]. High OX-40 expression in the tumor immune infiltrate is associated with favorable prognosis in non-small cell lung cancer, ovarian carcinoma, advanced gastric cancer, advanced colorectal cancer, melanoma, and glioblastoma [19–25]. Immunotherapy with OX40 agonists improves the survival of mice with glioblastoma, protects against tumor growth in ovarian cancer, and increases the prognostic significance of infiltration of CD8+ cells into colorectal carcinoma [23,26,27].
Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer
Published in OncoImmunology, 2021
Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Toraji Amano, Takayuki Ohkuri, Shigeo Yamazaki, Hajime Kikuchi, Satoshi Oizumi, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Masaharu Nishimura, Hiroyuki Suzuki, Hirotoshi Dosaka-Akita, Hiroshi Isobe
OX40, also known as CD134, is a member of the tumor necrosis factor superfamily. It resides on the surface of various immunological cells such as activated T lymphocytes and regulatory T cells (Tregs). OX40 engagement via the OX40 ligand (OX40L) mediates antitumor immunity via anti-apoptotic protein induction, effector T cell stimulation, and Treg suppression.6 However, conflicting clinical observations have been reported in this regard. Specifically, the infiltration of OX40+ T cells in tumors was related to better survival in patients with colon cancer7 and non-small cell lung cancer (NSCLC),8 but worse survival was observed in patients with hepatocellular carcinoma.9 Investigators, including us, have attempted to enhance OX40 signaling using OX40L fusion proteins and anti-OX40 agonistic monoclonal antibodies (mAbs) either individually or in combination with ICIs, other immunotherapy, or radiotherapy to establish a novel immunotherapeutic strategy in pre-clinical and clinical settings.6,10–12 However, the OX40 expression profile in SCLC remains relatively unknown. In addition, searching ClinicalTrials.gov using the terms “SCLC” and “OX40” revealed just one ongoing clinical trial and another completed clinical trial that included patients with advanced solid tumors including SCLC who were administered agonistic anti-OX40 monoclonal antibodies (NCT02554812 and NCT03241173, respectively as of August 1st, 2021). The findings of these trials are yet to be reported.
Immunogenicity risk assessment for biotherapeutics through in vitro detection of CD134 and CD137 on T helper cells
Published in mAbs, 2021
Sivan Cohen, Srividya Myneni, Anna Batt, Joyce Guerrero, Jochen Brumm, Shan Chung
To determine the robustness of this assay in the evaluation of the immunogenicity risk of various biotherapeutics, we tested 6 additional biotherapeutics with known low and high clinical ADA. We stimulated PBMCs from a cohort of 40 HLA-II typed donors, 26 of whom overlapped with those tested against HuA33 and bevacizumab (Supplementary Table 1), with biotherapeutic antibody-based drugs targeting PCSK9 that have a range of ADA rates (Table 1): bococizumab (48% ADA5), MPSK3169A/RG7652 (3.3% ADA26), alirocumab (4.8% 6.3% ADA;USPI 2017), or evolocumab (0.3% ADA; USPI 2017). We evaluated the abundance of CD134 and CD137 on CD4+ T cells. Consistent with the clinical data that identify bococizumab as having a higher immunogenicity risk than the other anti-PCSK9 antibodies, we found that 19 of the 40 (47.5%) donors were responsive to bococizumab, whereas no more than 3 of the 40 donors responded to RG7652, alirocumab, or evolocumab (Figure 2a and b).