黑色素瘤中的慢性抗原刺激会诱导T细胞耗竭,并限制T细胞双特异性疗法的疗效。
Chronic antigen stimulation in melanoma induces T cell exhaustion and limits efficacy of T cell bispecific therapies.
作者信息
Hutter-Karakoc Idil, Varypataki Eleni Maria, Neelakandhan Aparna, Lang Simone, Kramar Vesna, Varol Ahmet, Simons Sasha, Richard Marine, Pincha Mudita, Venetz Dario, Sam Johannes, Joller Nicole, Münz Christian, Umana Pablo, Klein Christian, Amann Maria
机构信息
Roche Innovation Center Zurich, Roche Pharma Research and Early Development (pRED), Schlieren, Switzerland.
Institute of Experimental Immunology, University of Zürich, Zurich, Switzerland.
出版信息
Oncoimmunology. 2025 Dec;14(1):2526444. doi: 10.1080/2162402X.2025.2526444. Epub 2025 Aug 26.
T cell bispecific antibodies (TCBs) have demonstrated promising results in patients with solid tumors, yet the immunological mechanisms influencing their efficacy require further investigation. T cell exhaustion, induced by prolonged antigen exposure, is known to compromise T cell-based immunotherapies, but its effect on TCB efficacy remains unclear. Herein, we assessed the TCB efficacy on tumor-specific T cells, emphasizing their functional status. Utilizing an immunocompetent mouse model with melanoma expressing an immunogenic antigen, we showed that tumor-specific T cells acquire an exhausted phenotype and fail to expand under TCB treatment. Both mouse and human tumor-specific T cells demonstrated that chronically stimulated T cells exhibit a reduced response to TCBs. The comparison of TCB efficacy in T cell-inflamed versus non-inflamed tumors in mice revealed TCB success depends more on T cell functional fitness than their initial abundance. These data underscore the importance of T cell exhaustion, suggesting that exhausted tumor-specific T cells are unlikely to be the primary effectors redirected by TCBs for tumor eradication. Our study highlights the need to maintain T cell fitness and prevent exhaustion to enhance TCB therapy outcomes, which may help identify patients who could benefit most from TCB treatments in clinics.
T细胞双特异性抗体(TCB)在实体瘤患者中已显示出有前景的结果,但其影响疗效的免疫机制仍需进一步研究。长期抗原暴露诱导的T细胞耗竭已知会损害基于T细胞的免疫疗法,但其对TCB疗效的影响仍不清楚。在此,我们评估了TCB对肿瘤特异性T细胞的疗效,重点关注其功能状态。利用具有表达免疫原性抗原的黑色素瘤的免疫活性小鼠模型,我们发现肿瘤特异性T细胞获得耗竭表型,并且在TCB治疗下无法扩增。小鼠和人类肿瘤特异性T细胞均表明,长期受刺激的T细胞对TCB的反应降低。对小鼠中T细胞炎症性肿瘤与非炎症性肿瘤中TCB疗效的比较表明,TCB的成功更多地取决于T细胞的功能适应性而非其初始丰度。这些数据强调了T细胞耗竭的重要性,表明耗竭的肿瘤特异性T细胞不太可能是TCB重定向用于根除肿瘤的主要效应细胞。我们的研究强调了维持T细胞适应性并防止耗竭以提高TCB治疗效果的必要性,这可能有助于在临床上识别最能从TCB治疗中获益的患者。