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Abstract：
The role of CD161+CD127+CD8+ T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8+ T cell subsets in NSCLC with diabetes. We recruited NSCLC patients (n = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS (p = 0.0069 and p = 0.012, respectively) and significantly lower CD8+ T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161+CD127+CD8+ T cells among CD8+T cells in NSCLC with diabetes before anti-PD-1 treatment (p = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment (p = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161+CD127+CD8+ T cells to CD8+T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161+CD127+CD8+ T cell subset compared to CD161+CD127-CD8+ T cells in NSCLC with diabetes. CD161+CD127+CD8+ T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161+CD127+CD8+ T cells to CD8+T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161+CD127+CD8+ T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes.
摘要：
CD161+CD127+CD8+T细胞在非小细胞肺癌(NSCLC)合并糖尿病患者中的作用尚待探讨。这项研究确定了患病率，表型,CD8+T细胞亚群在非小细胞肺癌合并糖尿病中的作用。我们招募了接受抗PD-1免疫治疗作为一线治疗的NSCLC患者（n=436）。无进展生存期（PFS），总生存期（OS），T细胞浸润,分析伴或不伴糖尿病的非小细胞肺癌患者的外周血免疫学特征。患有糖尿病的NSCLC患者表现出更短的PFS和OS（分别为p=0.0069和p=0.012），并显着降低CD8T细胞浸润。通过飞行时间（CyTOF）进行的质量细胞计数显示，在抗PD-1治疗前（p=0.0071）患有糖尿病的NSCLC中，CD8T细胞中CD161CD127CD8T细胞的百分比高于无糖尿病的NSCLC，并且这种趋势在抗PD-1治疗后继续（p=0.0393）。流式细胞术和多重免疫荧光证实，糖尿病NSCLC患者的CD161+CD127+CD8+T细胞与CD8+T细胞的比率明显高于非糖尿病NSCLC患者。RNA测序分析显示，与患有糖尿病的NSCLC中的CD161CD127-CD8T细胞相比，CD161CD127CD8T细胞亚群中的免疫细胞毒性基因减少。CD161+CD127+CD8+T细胞在糖尿病NSCLC中表现出更多的T细胞耗竭表型。CD161+CD127+CD8+T细胞与CD8+T细胞比率≥6.3%的糖尿病NSCLC患者PFS较差。这些发现表明糖尿病是接受抗PD-1免疫疗法的NSCLC患者的危险因素。CD161+CD127+CD8+T细胞可能是NSCLC合并糖尿病患者预后不良的关键指标。我们的发现将有助于推进抗PD-1治疗非小细胞肺癌患者的糖尿病。
