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Delivery of Immune Checkpoint Inhibitors Using Nanoparticles
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Abdullah Shaito, Houssein Hajj Hassan
Regulatory T cells (Tregs) have immunosuppressive functions and inhibit CTLs and other immune cells from performing antitumor effector functions against cancer cells. Elimination or suppression of Tregs can be used to induce anticancer immune responses by removing the inhibition of Tregs on CTLs. In one study, nanoparticles were used to deliver a combination of a Tregs inhibitory molecule (tLyp1 peptide) and a checkpoint inhibitor (CTLA-4 antibody). Administration of the combination NPs decreased the number of intra-tumoral Tregs, increased the number of tumor-specific CTLs, exhibited greater tumor suppression, and prolonged survival of mice injected with melanoma cells as compared to NPs carrying the Tregs inhibitor alone or the checkpoint inhibitor alone [3, 124]. This combination NP can be used in cancers that are resistant to checkpoint inhibition therapy, however, a thorough assessment of in vivo side effects should be warranted, as the risk for immune tolerance related adverse responses will increase.
Host Response to Biomaterials
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Sangeetha Srinivasan, Julia E. Babensee
TCRs recognize peptide fragments of antigens bound to MHC molecules. Naive TH cells require a second signal for generation of protective effector functions post TCR stimulation.95109 This second signal is provided by ligation of costimulatory molecules with B7 molecules on APCs. Upon APC maturation, CD80 and CD86 expressions are upregulated, thus supporting their immunostimulatory ability.111 The third signal of the cytokine environment polarizes T-cells responses. Absence of the second signal leads to T-cell anergy. T-cell polarization, for example, toward TH1 or TH2 phenotypes is achieved in response to secreted IL-12 or IL-4. Regulatory T-cells or Tregs with CD4+ CD25+ CTLA4+ or TGF-^-induced CD4+ CD25- FoxP3+112 have the ability of resolving immunity and promoting tolerance with specificity to antigen. The T-lymphocyte antigen 4 (CTLA4), a molecule homologous to CD28, binds to costimulatory B7 molecules.113114
Immunotherapy and Nanovaccines
Published in Sourav Bhattacharjee, Principles of Nanomedicine, 2019
These are T-cells-expressing biomarkers, such as CD25, CD4, and Foxp3 [29], which suppress the antitumor immune response by causing upregulation of antiapoptotic and downregulation of proapoptotic genes [30], often associated with cancers of liver, gonads, lungs, and head-neck [31–34]. Infiltration of the tumor tissue by regulatory T-cells (Tregs) indicates immunosuppression and usually a poor prognosis [35]. Tregs overexpress cytotoxic T lymphocyte–associated antigen-4, which interacts with CD80/86 in APCs to produce immunomodulatory agent indoleamine 2,3-dioxygenase. The immunosuppressor TGF-β is known to stimulate the Tregs [36].
Tumor growth suppression by implantation of an anti-CD25 antibody-immobilized material near the tumor via regulatory T cell capture
Published in Science and Technology of Advanced Materials, 2021
Tsuyoshi Kimura, Rino Tokunaga, Yoshihide Hashimoto, Naoko Nakamura, Akio Kishida
Cancer treatment can be classified into surgical treatment, chemotherapy, radiotherapy, and immunotherapy. Cancer immunotherapy is a method for treating cancer using the immune system. To date, various cancer immunotherapies have been proposed, including vaccine therapy using autologous cancer vaccines [1], dendritic cell vaccines [2], and adoptive immunotherapy using natural killer (NK) cells and cytotoxic T cells [3]. Among these approaches, cancer immunotherapy related to regulatory T cells (Tregs) has recently become a major research focus. Tregs, i.e., CD4-, CD25-, and FoxP3-positive T cells, are key players in immune suppression [4] and function by controlling the activation of antigen-presenting cells via cytotoxic T lymphocyte antigen (CTLA)-4 and immunosuppressive cytokines (e.g., interleukin-10). In addition, Tregs play roles in suppressing the attack of T cells and other immune cells by modulating the production of transforming growth factor-β [5]. Furthermore, in the tumor microenvironment, which is formed by various components, including cancer cells, immune cells, and the extracellular matrix, Treg accumulation is induced by secretion of the chemokine C-C motif chemokine ligand 22 (CCL22) from cancer cells and tumor-infiltrating macrophages, resulting in an antitumor immune response [6,7]. Several treatments that inhibit immunosuppressive signal transduction by immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-programmed death-1 antibodies) and depletion of Tregs by administration of anti-C-C motif chemokine receptor 4 antibodies have been proposed as Treg-related cancer immunotherapies [8,9]. The development of selective Treg removal methods is also proposed [10,11]. Although the efficacies of these treatments have been demonstrated, treatment with immune checkpoint inhibitors can induce serious side effects owing to activation of T cells [12]. In addition, because Tregs are strongly related to autoimmunity, Treg-removing treatments may cause systemic autoimmune diseases. Therefore, the development of a method for local Treg removal at the tumor is essential.