目的:免疫检查点抑制剂彻底改变了肾细胞癌(RCC)的治疗方法,但是许多患者对治疗没有反应,大多数患者随着时间的推移会出现耐药性疾病。因此,对替代免疫调节剂的需求日益增加。共抑制分子T细胞免疫球蛋白和ITIM结构域(TIGIT)可能在对批准的免疫检查点抑制剂的抗性中发挥作用,并且正在作为潜在的治疗靶标进行研究。这项研究的目的是量化RCC中肿瘤浸润T细胞的TIGIT阳性。
方法:我们采用了包含原发性肾癌肿瘤标本的组织微阵列,邻近的正常肾组织,和RCC转移使用定量免疫荧光分析定量肿瘤浸润性CD3+T细胞内的TIGIT。我们还将这些结果与其他四种肿瘤类型(黑色素瘤,非小细胞肺,子宫颈,和头颈癌)。
结果:我们没有观察到原发性RCC肿瘤和患者匹配的转移样本之间TIGIT阳性的显著差异。我们发现RCC的TIGIT阳性程度与肺癌相当,但低于黑色素瘤,子宫颈,头颈癌.将TIGIT阳性与先前发表的相关分析进行比较,我们小组的患者匹配的空间蛋白质组数据显示TIGIT与检查点蛋白PD-1和LAG3之间呈负相关.
结论:我们的研究结果支持对可能用TIGIT靶向抗体治疗的患者,对原发性或转移性肾癌标本中T细胞的TIGIT表达进行仔细评估,因为TIGIT阳性的增加可能与治疗应答的可能性更大相关。
OBJECTIVE: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (
TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify
TIGIT positivity in tumor-infiltrating T cells in RCC.
METHODS: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers).
RESULTS: We did not observe significant differences in
TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between
TIGIT and the checkpoint proteins PD-1 and LAG3.
CONCLUSIONS: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased
TIGIT positivity might be associated with a greater likelihood of response to therapy.