Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.
J Immunother Cancer. 2024 Jan 30;12(1):e008385. doi: 10.1136/jitc-2023-008385.
Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown.
Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor β-chain (TCRβ), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB).
Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRβ clonality (inverted Pielou's evenness) increased and TCRβ diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023).
Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer.
肿瘤相关抗原（TAA）特异性 CD8+T 细胞是纳武利尤单抗治疗的关键，有报道称放疗具有产生和激活 TAA 特异性 CD8+T 细胞的潜力。然而，放疗联合纳武利尤单抗的组合免疫治疗中 T 细胞反应的机制仍知之甚少。
本研究纳入了 CIRCUIT 试验中的 20 名患者（ClinicalTrials.gov，NCT03453164）。所有患者均有多发性远处转移，在接受一线和二线化疗后出现不耐受或进展，且未接受任何免疫检查点抑制剂治疗。在 CIRCUIT 试验中，符合条件的患者在接受纳武利尤单抗每 2 周一次治疗前，先接受最大或有症状病灶 22.5Gy/5 次分割/5 天的放疗。在这 20 名患者中，通过高维流式细胞术基于多重主要组织相容性复合物三聚体分析，使用总共 46 个 TAA 和 10 个病毒表位，T 细胞受体 β 链（TCRβ）的 repertoire 分析，以及循环肿瘤 DNA 分析来监测组合免疫治疗中的 T 细胞反应，以评估肿瘤突变负荷（TMB）。
尽管大多数 TAA 特异性 CD8+T 细胞可以进行纵向跟踪，但在放疗后也检测到了几个新出现的 TAA 特异性 CD8+T 细胞，但病毒特异性 CD8+T 细胞在治疗过程中没有明显变化，表明潜在的放疗驱动抗原扩散。放疗与 TAA 特异性 CD8+T 细胞的表型变化有关，表现为杀伤细胞凝集素样受体亚家族 G，成员 1、人类白细胞抗原相关抗原、T 细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域、CD160 和 CD45RO 的表达增加，而 CD27 和 CD127 的表达降低。重要的是，与进展者相比，非进展者的 TAA 特异性 CD8+T 细胞经常表现为 CD45RO+CD27+CD127+中央记忆 T 细胞的表型。在进展者中，TCRβ克隆性（倒皮尔洛均匀度）增加（p=0.029），TCRβ多样性（皮尔洛均匀度和多样性均匀度评分）降低（p=0.029，p=0.012）。在放疗后，非进展者的 TMB 评分明显降低（p=0.023）。
分次放疗诱导出具有潜在抗原扩散的免疫调节作用，放疗联合纳武利尤单抗可能对胃癌的一部分患者有效。
