Leveraging TCR Affinity in Adoptive Immunotherapy against Shared Tumor/Self-Antigens.
Leveraging TCR Affinity in Adoptive Immunotherapy against Shared Tumor/Self-Antigens.
复制标题
DOI：
10.1158/2326-6066.cir-18-0371
复制
发表时间：
2019-01
影响因子：
10.1
通讯作者：
Schoenberger SP
中科院分区：
文献类型：
--
作者：
Miller AM;Bahmanof M;Zehn D;Cohen EEW;Schoenberger SP
使用t细胞受体（TCR）工程淋巴细胞的过继细胞疗法（ACT）有望根除播散性肿瘤，但如果靶向抗原或抗原模拟物在正常组织中表达，也存在病理性自身免疫的固有风险。在临床前小鼠ACT模型中，我们评估了调节TCR亲和力是否可以使CD8+ T细胞控制肿瘤生长而不诱导伴随的自身免疫。RIP-mOVA小鼠在肾脏和胰腺中表达一种膜结合形式的鸡卵蛋白（mOVA）作为自身抗原。这些小鼠被植入表达ova的ID8卵巢癌细胞，随后用表达高亲和力（OT-I）或低亲和力（OT-3） ova特异性TCR的CD8+ T淋巴细胞（ctl）治疗。随后监测对肿瘤生长和器官特异性自身免疫的影响。高亲和力的OT-I ctl在肿瘤引流和胰腺淋巴结中都经历了激活和增殖，导致所有治疗小鼠ID8-OVA肿瘤和自身免疫性糖尿病的快速根除。值得注意的是，低亲和力的ot - 3t细胞仅被肿瘤源性抗原激活，并介导ID8-OVA肿瘤的短暂消退，而不伴有自身免疫。然而，OT-3细胞最终上调了抑制受体PD-1、TIM-3和LAG-3，并在功能上变得无反应，从而使治疗小鼠的肿瘤重新建立进行性生长。抗体介导的抑制受体阻断阻止了衰竭并允许肿瘤清除，但这些小鼠也发展为自身免疫性糖尿病。研究结果表明，低亲和力TCRs可以介导肿瘤消退，功能亲和性可以区分肿瘤源性抗原和内源性抗原，同时强调了免疫检查点阻断内源性自反应性T细胞的风险。
Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors, but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas. Such mice were implanted with OVA-expressing ID8 ovarian carcinoma cells and subsequently treated with CD8+ T lymphocytes (CTLs) expressing either a high-affinity (OT-I) or low-affinity (OT-3) OVA-specific TCR. The effects on tumor growth versus organ-specific autoimmunity were subsequently monitored. High-affinity OT-I CTLs underwent activation and proliferation in both tumor-draining and pancreatic lymph nodes, leading to both rapid eradication of ID8-OVA tumors and autoimmune diabetes in all treated mice. Remarkably, the low-affinity OT-3 T cells were only activated by tumor-derived antigen and mediated transient regression of ID8-OVA tumors without concomitant autoimmunity. The OT-3 cells eventually upregulated inhibitory receptors PD-1, TIM-3, and LAG-3 and became functionally unresponsive, however, allowing the tumors in treated mice to reestablish progressive growth. Antibody-mediated blockade of the inhibitory receptors prevented exhaustion and allowed tumor clearance, but these mice also developed autoimmune diabetes. The findings reveal that low-affinity TCRs can mediate tumor regression and that functional avidity can discriminate between tumor-derived and endogenous antigen, while highlighting the risks involved in immune checkpoint blockade on endogenous self-reactive T cells.