Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA.
Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2022-004803.
Checkpoint therapy is now the cornerstone of treatment for patients with renal cell carcinoma (RCC) with advanced disease, but biomarkers are lacking to predict which patients will benefit. This study proposes potential immunological biomarkers that could developed for predicting therapeutic response in patients with RCC.
Using flow cytometry, RNA sequencing, and T-cell receptor (TCR) sequencing, we investigated changes in T cells in the peripheral blood of patients with advanced RCC after receiving immunotherapy. We used immunofluorescence (IF) imaging and flow cytometry to investigate how intratumoral T cells in patients' tumors (resected months/years prior to receiving checkpoint therapy) predicted patient outcomes after immunotherapy.
We found that a small proportion of CD4 and CD8 T cells in the blood activate following checkpoint therapy, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR +CD38+CD8 T cells after treatment had the best antitumor immune response and experienced clinical benefit. Using RNA sequencing, we found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR +CD38+CD8+T cells, we found that only patients who clinically benefitted had a burst of new clonotypes enter this pool of activated cells. Finally, we found that abundant T cells in the untreated tumors predicted clinical benefit to checkpoint therapy on disease progression.
Together, these data suggest that having a strong pre-existing immune response and immediate peripheral T-cell activation after checkpoint therapy is a predictor of clinical benefit in patients with RCC.
检查点疗法现已成为晚期肾细胞癌（RCC）患者治疗的基石，但缺乏预测哪些患者将从中受益的生物标志物。本研究提出了潜在的免疫生物标志物，可用于预测 RCC 患者的治疗反应。
使用流式细胞术、RNA 测序和 T 细胞受体（TCR）测序，我们研究了接受免疫治疗后晚期 RCC 患者外周血中 T 细胞的变化。我们使用免疫荧光（IF）成像和流式细胞术来研究患者肿瘤内的 T 细胞（在接受检查点治疗前数月/数年前切除）如何预测免疫治疗后的患者结局。
我们发现，一小部分 CD4 和 CD8 T 细胞在接受检查点治疗后会激活，表达增殖标志物 Ki67 以及激活标志物 HLA-DR 和 CD38。治疗后这些 HLA-DR + CD38 + CD8 T 细胞增加最多的患者具有最佳的抗肿瘤免疫反应，并获得临床获益。使用 RNA 测序，我们发现尽管这些细胞在大多数患者中扩增，但在治疗过程中其表型并未发生明显变化。然而，当我们分析这些 HLA-DR + CD38 + CD8 + T 细胞的 TCR 库时，我们发现只有临床获益的患者才有大量新的克隆型进入该激活细胞池。最后，我们发现未经治疗的肿瘤中存在丰富的 T 细胞预示着对检查点治疗的疾病进展具有临床获益。
综上所述，这些数据表明，在接受检查点治疗后存在强烈的预先存在的免疫反应和外周 T 细胞的即刻激活是预测 RCC 患者临床获益的指标。
