Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Front Immunol. 2024 May 10;15:1396719. doi: 10.3389/fimmu.2024.1396719. eCollection 2024.
Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2 TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker.
We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2 TAM subpopulations (CD68SHP2, CD68CD86, CD68 + 206, CD68 CD86SHP2, CD68 CD206SHP2) and T cells (CD8 Granzyme B ) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests.
In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68 SHP2 TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68SHP2 TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68SHP2 subset proportion was positively correlated with the CD68CD206 subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001).
The high infiltration of CD68SHP2 TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.
肿瘤相关巨噬细胞（TAMs）构成肿瘤微环境（TME）中具有可塑性和异质性的细胞群体，可调节肿瘤增殖并支持对治疗的耐药性，因此成为开发新型抗癌药物的有前途的靶点。我们之前的研究结果表明，SHP2 在重编程 TAMs 的表型中起关键作用。因此，我们假设 SHP2 TAM 可以作为生物标志物预测非小细胞肺癌（NSCLC）患者的治疗效果。
我们使用多重荧光（mIF）染色分析了 79 名 NSCLC 患者的癌症组织样本，以可视化各种 SHP-2 TAM 亚群（CD68SHP2、CD68CD86、CD68+206、CD68CD86SHP2、CD68CD206SHP2）和 T 细胞（CD8 Granzyme B）。在肿瘤区域（肿瘤）和基质区域（基质）以及整个肿瘤微环境（肿瘤和基质，TME）中定量了免疫细胞的比例。分析终点为总生存期（OS），并将其与细胞浸润或有效密度相关联。Cox 回归用于评估免疫细胞亚群浸润与 OS 之间的关联。使用 Spearman 检验检查不同免疫细胞亚群之间的相关性。
在 NSCLC 中，TME、肿瘤区域和基质区域内不同巨噬细胞亚群的分布不一致。CD68 SHP2 TAMs 的比例（P <0.05）在肿瘤中高于基质。并且肿瘤区域中 CD68SHP2 TAMs 的高浸润与不良 OS 相关（P <0.05）。我们发现 SHP2 的表达水平在 M2 样巨噬细胞中高于 M1 样巨噬细胞。CD68SHP2 亚群比例与 TME（P <0.0001）、肿瘤（P <0.0001）和基质（P <0.0001）内的 CD68CD206 亚群呈正相关。
CD68SHP2 TAMs 的高浸润预示着 NSCLC 的不良 OS。靶向 SHP2 可能是抑制 M2 表型极化的有效策略。这为 SHP2 靶向癌症免疫治疗提供了新的思路。
