Department of Biological Sciences, College of Natural and Social Sciences, California State University, Los Angeles (CSULA), 5151 State University Drive, Los Angeles, CA 90032, USA.
Department of Life Sciences, Los Angeles City College (LACC), 855 N. Vermont Ave., Los Angeles, CA 90029, USA.
Int J Mol Sci. 2021 Oct 29;22(21):11726. doi: 10.3390/ijms222111726.
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.
转移性黑色素瘤是导致皮肤癌相关死亡的主要原因。由于传统治疗方法无法有效地诱导肿瘤高比例消退，因此效果不佳。新型治疗方法，如免疫检查点抑制剂（ICI）、靶向治疗（BRAFi 和 MEKi）和 TCR 工程化 T 细胞，旨在提高宿主免疫系统识别和消除肿瘤的能力。ICI 抑制负性调节机制，增强宿主免疫系统的抗肿瘤活性，而针对异常信号分子（BRAF 和 MEK）的靶向治疗将阻断黑色素瘤的失控增殖和扩张。TCR 工程化 T 细胞策略的基础是将抗原特异性 TCRα/β 链转导到宿主 T 细胞中，产生针对肿瘤相关抗原的高亲和力 T 细胞。TCR 转基因 T 细胞在体外扩增和激活，并回输给患者，以增加癌细胞的靶向性。虽然这些治疗方法取得了不同程度的有利结果，但由于固有或获得性耐药性，其疗效有限。各种机制解释了黑色素瘤的免疫抵抗性，包括 MHC/肽复合物的丢失或下调、信号通路的异常活性以及凋亡机制的动态改变。这些机制共同使黑色素瘤对 T 细胞传递的凋亡刺激产生耐药性，尽管宿主具有完全功能和有效的抗肿瘤免疫反应。鉴定生物标志物、联合治疗和使用 CAR T 细胞是潜在规避黑色素瘤对免疫疗法耐药性的方法之一。
