Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China.
Department of Oncology and Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32 1st Ring Road, Chengdu, 610072, China.
Cancer Immunol Immunother. 2024 Jun 4;73(8):147. doi: 10.1007/s00262-024-03737-y.
This study aimed to investigate the relationship between signal regulatory protein gamma (SIRPG) and tumor immune microenvironment phenotypes or T cell mediated-adaptive antitumor immunity, and its predictive value for response to PD-1 blockade in cancers.
Pan-cancer analysis of SIRPG expression and immune deconvolution was performed using transcriptomic data across 33 tumor types. Transcriptomic and clinical data from 157 patients with non-small-cell lung cancer (NSCLC) and melanoma received PD-1 blockade were analyzed. Expression characteristics of SIRPG were investigated using single-cell RNA sequencing (scRNA-seq) data of 103,599 cells. The effect of SIRPG expression was evaluated via SIRPG knockdown or overexpression in Jurkat T cells.
The results showed that most cancers with high SIRPG expression had significantly higher abundance of T cells, B cells, NK cells, M1 macrophages and cytotoxic lymphocytes and increased expression level of immunomodulatory factors regulating immune cell recruitment, antigen presentation, T cell activation and cytotoxicity, but markedly lower abundance of neutrophils, M2 macrophages, and myeloid-derived suppressor cells. High SIRPG expression was associated with favorable response to PD-1 blockade in both NSCLC and melanoma. scRNA-seq data suggested SIRPG was mainly expressed in CD8 exhausted T and CD4 regulatory T cells, and positively associated with immune checkpoint expression including PDCD1 and CTLA4. In vitro test showed SIRPG expression in T cells could facilitate expression of PDCD1 and CTLA4.
High SIRPG expression is associated with an inflamed immune phenotype in cancers and favorable response to PD-1 blockade, suggesting it would be a promising predictive biomarker for PD-1 blockade and novel immunotherapeutic target.
本研究旨在探讨信号调节蛋白γ（SIRPG）与肿瘤免疫微环境表型或 T 细胞介导的适应性抗肿瘤免疫之间的关系，及其对癌症患者接受 PD-1 阻断治疗反应的预测价值。
采用 33 种肿瘤的转录组数据进行 SIRPG 表达和免疫分解的泛癌分析。分析了 157 例接受 PD-1 阻断治疗的非小细胞肺癌（NSCLC）和黑色素瘤患者的转录组和临床数据。利用 103599 个细胞的单细胞 RNA 测序（scRNA-seq）数据研究 SIRPG 的表达特征。通过 Jurkat T 细胞中的 SIRPG 敲低或过表达来评估 SIRPG 表达的影响。
结果表明，SIRPG 高表达的大多数癌症中，T 细胞、B 细胞、NK 细胞、M1 巨噬细胞和细胞毒性淋巴细胞的丰度显著更高，调节免疫细胞募集、抗原呈递、T 细胞激活和细胞毒性的免疫调节因子的表达水平也更高，而中性粒细胞、M2 巨噬细胞和髓源性抑制细胞的丰度显著更低。SIRPG 高表达与 NSCLC 和黑色素瘤患者对 PD-1 阻断治疗的良好反应相关。scRNA-seq 数据表明，SIRPG 主要在 CD8 耗尽 T 细胞和 CD4 调节性 T 细胞中表达，与包括 PDCD1 和 CTLA4 在内的免疫检查点表达呈正相关。体外试验表明，T 细胞中的 SIRPG 表达可促进 PDCD1 和 CTLA4 的表达。
SIRPG 高表达与癌症中的炎症免疫表型和对 PD-1 阻断的良好反应相关，表明其可能成为 PD-1 阻断和新型免疫治疗的有前途的预测生物标志物和新的免疫治疗靶点。
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