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Recent Advances of Nanotechnologies for Cancer Immunotherapy Treatment
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Immune checkpoint inhibitors have emerged as the hot spot in tumor immunotherapy recently. PD-1 is one of the most important immune checkpoint molecules and is overexpressed on activated T lymphocytes and has a tight correlation with tumor-associated immune suppression. In a normal situation, combination of PD-1 and PD-L1 can transmit inhibitory signals and reduce the proliferation of CD8+ T cells in lymph nodes, and PD-1 can also control the accumulation of antigen-specific T cells in lymph nodes by regulating the bcl-2 gene, thus protecting normal tissue from attacking under autoimmunity [139–141]. However, tumor cells could also escape from immune attack by overexpressing the PD-L1. Similarly, CTLA-4 could induce T lymphocytes to be nonreactive and negatively regulate the immune response after its incorporation with B7 expressed on activated APCs [142,143]. The immune checkpoint inhibitors including anti-CTLA4 and anti-PD-1/PD-L1 antibodies have entered into clinical treatments and showed impressive curative effects; however, the efficacy is still limited by the relatively low rate of the treatment response and high incidence of side effects. Therefore, nanoparticles are considered for the delivery of these drugs in a targeted and sustainable-releasing pattern, thus reducing the treatment dose and decreasing side effects.
Aptamers and Cancer Nanotechnology
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Omid C. Farokhzad, Sangyong Jon, Robert Langer
Cytotoxic T-cell antigen-4 (CTLA-4) is a transmembrane protein that is expressed on the surface of activated T-cells and functions to attenuate the T-cell response by raising the threshold needed for T-cell activation. D60 (Kd = 33 nM) is a size-minimized, 35-base-pair, 2′-fluoropyrimidine modified nuclease stable RNA aptamer that was selected against CTLA-4 and shown to inhibit CTLA-4 function in vitro and enhance tumor immunity in mice.66
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Another interesting mechanism of cancer (stem) cells is the manipulation of the body’s immune cells to guarantee their own survival. For this purpose, tumor cells express molecules on their cell surface (B7, PD-L1, or PD-L2), which allows them to functionally control T-cells and other immune cells (Iwai et al., 2002). In most cases, PD-L1 is the key molecule expressed on solid tumors. This ligand binds to PD-1 on T-cells, a functional homolog of CTLA-4, and represses any T-cell activity directed towards the tumor cell. Basically, T cells are initially very strongly activated by several signaling pathways, including TCR/CD3, CD28, and IL2R. However, T-cell effector functions are usually active only for a couple of days, until the surface receptor CD28 is being exchanged into CTLA-4. CTLA-4 (like PD-1) signaling is blocking T cell effector functions and initiates the important homeostatic phase of any immune reactions. When tumor cells express PD-L1 on their surface, they simply trigger down any T-cell activity which could be harmful for them (Norde et al., 2011). Thus, a tumor cell can be surrounded by hundreds of T-cells, but none of them will attack the corresponding tumor cell when expressing PD-L1. This knowledge has led to the development of “checkpoint inhibitors,” specific antibodies blocking the PD-1::PD-L1 interaction, as novel drugs to re-activate T-cell functions directed against tumor cells (as described by Suzuki et al., 2014; Callahan and Wolchok, 2013). Interestingly, this new type of therapy was quite successful in those cancer types that express many neoantigens, like melanoma, different lung cancers, and different gastro-intestinal tumors (Schumacher and Schreiber, 2015). This is an interesting point to acknowledge, because if a tumor is too similar to normal host cells, it may prevent the attack of its own immune system (see Fig. 17.1, lower right panel).
An immune cell infiltration landscape classification to predict prognosis and immunotherapy effect in oral squamous cell carcinoma
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
The ICI scores were not only associated with prognosis but also a novel biomarker for immunotherapy independent of TMB. Current studies suggest that multiple biomarkers may be used to predict the efficacy of immunotherapy (Gavrielatou et al. 2020). Wang et al. found that CD8+ T and CD4+ T cells were significantly increased, and the aggregation of CT-LA-4+ T cells in the microenvironment of 4-nitroquinoline 1-oxide induced oral cancer mouse models after the use of PD-1 blocking antibodies. PD-1 inhibits the induced activation associated with IFN -γ and STAT1, suggesting that T cell activation mediates the immunoprotective effect against PD-1. The findings demonstrated that CTLA-4 might be utilized as a biomarker to predict the efficacy and the CTLA-4 inhibitors can improve anti-PD-1 regulation, thus evaluating the effectiveness of immunotherapy (Wang et al. 2017). Furthermore, some defects, mutations, and physiological and pathological states in vivo can also be used as biomarkers to predict the efficacy of immunotherapy. Microsatellite Instability (MSI) and Mismatch Repair Defect (MMRD), for example, are hypermutated phenotypes. The high immunogenicity of tumors with MSI and MMRD characteristics has been used as a predictive biomarker of ICI’s efficacy and demonstrated in clinical trials against PD-1 (Chalmers et al. 2017).
Modelling combined virotherapy and immunotherapy: strengthening the antitumour immune response mediated by IL-12 and GM-CSF expression
Published in Letters in Biomathematics, 2018
Adrianne L. Jenner, Chae-Ok Yun, Arum Yoon, Adelle C. F. Coster, Peter S. Kim
Controlling the CTL induced apoptosis rates k could be achieved through the introduction of an experimental cancer treatment known as CTLA-4 blockades (Henson, Macaulay, Kiani-Alikhan, & Akbar, 2008; Parry et al., 2005). CTLA-4 is a well-known T cell inhibitory B7-receptor that is expressed by activated T cells. Using the CTLA-4 blockade, researchers have shown that this treatment can enhance T cell cytotoxic responses and induce the differentiation of cytotoxic CD4 T cells Leach et al. (1996). Therefore, one possible way to investigate whether perturbations in the CTL induced apoptosis rates k would result in the outcomes presented in Figure 3(e), would be to look at combining CTLA-4 blockades with oncolytic virus expressing IL-12 and GM-CSF.