黑色素瘤对 TCR 工程化过继细胞治疗不敏感的分子要素分析

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 TCR / 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.