Predicting and Increasing Response of Melanoma to Interferon Therapy
Sanjiv S. Agarwala, Vernon K. Sondak in Melanoma, 2008
In 20 patients, HDI was investigated in the neoadjuvant setting (24). Immunohistochemical (IHC) analysis of tumor tissue revealed that HDI did not appear to influence the tumor cell phenotype, proliferation rate, or apoptotic fraction of cells in tumor biopsies and did not significantly affect tumor vasculature, irrespective of clinical response. In contrast, IHC analysis of immunological markers including T lymphocytes (CD3, CD4, and CD8), NK cells (CD56), and dendritic cells (CD11c, CD83, and CD86) showed that clinical response to HDI was consistently associated with augmented numbers of mononuclear immune cells infiltrating the tumor, but not those in the peritumoral or perivascular cellular compartments. These changes exhibited strong trends approaching nominal significance regarding CD3 and CD11c as well as CD83/86-positive populations.
Genetics, immunology, and pathogenesis
M. Alan Menter, Caitriona Ryan in Psoriasis, 2017
On a histopathologic level, the sequence may occur as follows (see Figure 13.2)65: (1) A genetically susceptible host is exposed to an environmental stimulus (e.g., trauma or infection). (2) Damage to keratinocyte results in release of antigenic material (e.g., antimicrobial peptides) that activates the innate immune response, possibly via binding to Toll-like receptors. (3) Plasmacytoid dendritic cells and other innate cells located in the epidermis are activated and produce proinflammatory cytokines (e.g., IFN-α, TNF-α). (4) These cytokines stimulate myeloid dendritic cells (CD83+) located in the dermis, which subsequently migrate to lymph nodes and present antigen to T cells. (5) T cells are activated by antigen presentation and subsequently proliferate (adaptive immunity). The cytokine milieu favors increased production of Th17 and Th1 cells resulting in an inflammatory response. (6) T cells migrate to the tissues (e.g., skin and synovium) where they perpetuate a chronic inflammatory immune response (e.g., keratinocyte hyperproliferation and synovitis). (7) The overexpression of proinflammatory cytokines results in activation of transcription factors and upregulation of proinflammatory genes. (8) A self-sustaining loop results in a chronic systemic inflammatory process.
Role of dendritic cells in integrating immune responses to luminal antigens
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
Study of DCs and macrophages in humans with IBD has been limited largely to inflamed tissue and blood cells, resulting in incomplete characterization of cDCs with nonspecific surface markers. Despite limited information, possible roles of DCs in IBD are shown in Figure 12.7. In humans, activated cDCs accumulate along with macrophages at sites of mucosal inflammation. In Crohn's disease tissue, DCs that express CD83, a glycoprotein associated with DC activation, are present in association with numerous CD83− CD80+ DC-SIGN+ DCs, producing IL-12 and IL-18. The expression of TLR2, TLR4, and CD40 is enhanced in DCs isolated from inflamed mucosa that also overproduce IL-6 and IL-12. Furthermore, mature DCs recruited to the lamina propria form clusters with proliferating T cells in the affected colonic tissue. In ulcerative colitis, an increase in activated CD83+ cells produces macrophage inhibitory factor (MIF), which is thought to contribute to neutrophil recruitment and activation.
High dose dexamethasone as an alternative rescue therapy for active bleeding in children with chronic ITP: clinical and immunological effects
Published in Platelets, 2019
Mervat A M Youssef, Eman Salah Eldeen, Khalid I Elsayh, Samaher F Taha, Mohamed Gamil M Abo-Elela
CD83 is a maturation marker for DCs that can modulate the immune response by activating DC via sending co-stimulatory signals for stimulation of naive and memory T cells [40]. DXM downregulated the CD83 expression on DCs and inhibit IL-12p70, TNF-α, especially IFN-γ [37]. DXM reduced expression of CD83 when incubated with immature DCs and reduced the DC ability to stimulate allogeneic T cell proliferation in proportion to the level of CD14+, CD83 + cells in the population. CD83 cells, from patients treated with DXM, retained IL-12 production and the capability to stimulate the allogeneic T cell proliferation [35]. In the current study, ITP children exhibited a reduction in CD83 expression after a short course of HD-DXM, which may explain the acute upgrading in the platelet level.
Neoadjuvant treatments in patients with high-risk resectable stage III/IV melanoma
Published in Expert Review of Anticancer Therapy, 2020
Francesco Spagnolo, Elena Croce, Andrea Boutros, Enrica Tanda, Federica Cecchi, Matteo Mascherini, Nicola Solari, Ferdinando Cafiero, Paola Queirolo
In a neoadjuvant study reported by Moschos et al., 20 patients with palpable regional lymph node metastases (stage IIIB-C according to AJCC 7th edition) [36] were enrolled and received intravenous high-dose Interferon-alpha-2b (HDI) at 20 MU/m2 5 days per week for 4 weeks, followed by complete lymphadenectomy and maintenance with subcutaneous HDI (10 MU/m2, 3 times per week) for 48 weeks. Fifty-five percent of the patients achieved an objective clinical response, and 15% a pCR. However, only 10 patients were disease free at a median follow up of 18.5 months [28]. To elucidate the effects of neoadjuvant treatment on tumor microenvironment, patients underwent surgical biopsy at study entry before the administration of HDI. Interestingly, patients who achieved a clinical response had significantly greater increases in CD11 c+ and CD3+ cells and significantly greater decreases in CD83+ cells compared to those who did not achieve a response, while no changes were observed in the expression of melanoma-associated lineage antigens, tumor cell proliferation, or apoptosis, implying an indirect immunomodulatory mechanism rather than a direct antitumor effect [28].
Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy
Published in Expert Opinion on Investigational Drugs, 2021
DCs function as antigen-presenting cells (APCs) which play an integral role in activation of the adaptive immune response. DCs are broadly categorized into two subsets: classical or conventional DCs (cDCs) and plasmacytoid DCs (pDC). cDCs originate from bone marrow precursors and have potent phagocytic properties [36]. In the TME, DCs activate the T cell response by capturing, processing, and cross-presenting neoantigens. However, tumor cells can transform DCs to an immature, immunosuppressive phenotype [37]. In CCA, infiltration of mature CD83+ DCs correlated with aggregation of CD4+/CD8+ T cells in the peritumoral region [38]. The presence of CD83+ DCs was also associated with improved patient outcomes. In contrast, the presence of CD1a (immature) DCs in the central tumor region is associated with a paucity of CD4+/CD8+ T cells [38]. FcεRI, a high-affinity immunoglobulin E receptor, is employed by DCs for cross presentation and priming of CTLs [39]. There is a significant decrease in FcεRI+ monocytes and DCs in the peripheral blood of patients with CCA [40]. These findings indicate that DCs are dysfunctional in CCA and unable to restrain tumor progression.
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