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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Autor principal:	Ali R. Jazirehi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	apoptosis signal transduction molecular targeted therapy T cell receptor vemurafenib melanoma Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/08d8d2464a0546888f21b6f041850536
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spelling	oai:doaj.org-article:08d8d2464a0546888f21b6f0418505362021-11-11T17:10:59ZMolecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy10.3390/ijms2221117261422-00671661-6596https://doaj.org/article/08d8d2464a0546888f21b6f0418505362021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11726https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Metastatic 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.Ali R. JazirehiMDPI AGarticleapoptosissignal transductionmolecular targeted therapyT cell receptorvemurafenibmelanomaBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11726, p 11726 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	apoptosis signal transduction molecular targeted therapy T cell receptor vemurafenib melanoma Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	apoptosis signal transduction molecular targeted therapy T cell receptor vemurafenib melanoma Biology (General) QH301-705.5 Chemistry QD1-999 Ali R. Jazirehi Molecular Analysis of Elements of Melanoma Insensitivity to TCR-Engineered Adoptive Cell Therapy
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.
format	article
author	Ali R. Jazirehi
author_facet	Ali R. Jazirehi
author_sort	Ali R. Jazirehi
title	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_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_sort	molecular analysis of elements of melanoma insensitivity to tcr-engineered adoptive cell therapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/08d8d2464a0546888f21b6f041850536
work_keys_str_mv	AT alirjazirehi molecularanalysisofelementsofmelanomainsensitivitytotcrengineeredadoptivecelltherapy
_version_	1718432160405258240

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

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