Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy

Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell recep...

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Main Author: Ali R. Jazirehi
Format: Article
Language:English
Published: MDPI AG 2021-10-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/21/11726
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author Ali R. Jazirehi
author_facet Ali R. Jazirehi
author_sort Ali R. Jazirehi
collection DOAJ
description Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell receptor (TCR)-engineered T cells aim to increase the ability of the host immune system to recognize and eradicate tumors. ICIs inhibit negative regulatory mechanisms and boost the antitumor activity of the host’s immune system, while targeted therapy directed against aberrant signaling molecules (BRAF and MEK) will block the uncontrolled proliferation and expansion of melanomas. The basis of the TCR-engineered T cell strategy is to transduce host T cells with antigen-specific TCRα/β chains to produce high-affinity T cells for tumor-associated antigens. TCR-transgenic T cells are expanded and activated ex vivo and reinfused into patients to increase the targeting of cancer cells. While these treatments have had varyingly favorable results, their efficacy is limited due to inherent or acquired resistance. Various mechanisms explain melanoma immune-resistance, including the loss or downregulation of the MCH/peptide complex, aberrant activity of signaling pathways, and altered dynamics of apoptotic machinery. Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma’s resistance to immunotherapy.
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spelling doaj.art-08d8d2464a0546888f21b6f0418505362023-11-22T20:56:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211172610.3390/ijms222111726Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell TherapyAli R. Jazirehi0Department of Biological Sciences, College of Natural and Social Sciences, California State University, Los Angeles (CSULA), 5151 State University Drive, Los Angeles, CA 90032, USAMetastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), targeted therapy (BRAFi and MEKi), and T cell receptor (TCR)-engineered T cells aim to increase the ability of the host immune system to recognize and eradicate tumors. ICIs inhibit negative regulatory mechanisms and boost the antitumor activity of the host’s immune system, while targeted therapy directed against aberrant signaling molecules (BRAF and MEK) will block the uncontrolled proliferation and expansion of melanomas. The basis of the TCR-engineered T cell strategy is to transduce host T cells with antigen-specific TCRα/β chains to produce high-affinity T cells for tumor-associated antigens. TCR-transgenic T cells are expanded and activated ex vivo and reinfused into patients to increase the targeting of cancer cells. While these treatments have had varyingly favorable results, their efficacy is limited due to inherent or acquired resistance. Various mechanisms explain melanoma immune-resistance, including the loss or downregulation of the MCH/peptide complex, aberrant activity of signaling pathways, and altered dynamics of apoptotic machinery. Collectively, these mechanisms confer melanoma resistance to apoptotic stimuli delivered by T cells despite a fully functional and effective antitumor immune response. Identification of biomarkers, combination treatment, and the use of CAR T cells are among the approaches that can potentially circumvent melanoma’s resistance to immunotherapy.https://www.mdpi.com/1422-0067/22/21/11726apoptosissignal transductionmolecular targeted therapyT cell receptorvemurafenibmelanoma
spellingShingle Ali R. Jazirehi
Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
International Journal of Molecular Sciences
apoptosis
signal transduction
molecular targeted therapy
T cell receptor
vemurafenib
melanoma
title Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
title_full Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
title_fullStr Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
title_full_unstemmed Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
title_short Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
title_sort molecular analysis of elements of melanoma insensitivity to tcr engineered adoptive cell therapy
topic apoptosis
signal transduction
molecular targeted therapy
T cell receptor
vemurafenib
melanoma
url https://www.mdpi.com/1422-0067/22/21/11726
work_keys_str_mv AT alirjazirehi molecularanalysisofelementsofmelanomainsensitivitytotcrengineeredadoptivecelltherapy