破译化疗诱导的肿瘤微环境(TME)中调节性T细胞(Tregs)的调节是至关重要的。这可能有助于提高新辅助化学免疫疗法在可切除的非小细胞肺癌(NSCLC)中的疗效。我们回顾性收集II-IIINSCLC患者的标本,构成两个队列:新辅助化疗(NAC)队列(N=141)活检(N=58)和术后标本(N=141),和仅手术队列(N=122)作为对照组。然后,细胞密度(Dens),入渗评分(InS),和Treg细胞接近度评分(TrPS)使用一组多重荧光染色(Foxp3,CD4,CD8,CK,CD31,符合SMA)。随后,分析了Tregs与癌微血管(CMV)和癌相关成纤维细胞(CAFs)的相关性.接受NAC治疗的患者在配对(P<0.001)和非配对分析(P=0.022)中都有较高的Treg密度。此外,接受NAC治疗的患者表现出更高的浸润评分(配对,P<0.001;未配对,P=0.014)和更多的CD8+T细胞周围的Tregs(配对/未配对,两者P<0.001)。亚组分析表明,直径≤5cm的肿瘤表现出Dens(Treg)和InS(Treg)的增加,和吉西他滨,培美曲塞和紫杉醇增强NAC后的Dens(Treg)和TrPS(CD8)。多变量分析确定Dens(Tregs),InS(Tregs)和TrPS(CD8)与更好的化疗反应显着相关[OR=8.54,95CI(1.69,43.14),P=0.009;OR=7.14,95CI(1.70,30.08),P=0.024;OR=5.50,95CI(1.09,27.75),P=0.039,分别]和阳性无复发生存率[HR=3.23,95CI(1.47,7.10),P=0.004;HR=2.70;95CI(1.27,5.72);P=0.010;HR=2.55,95CI(1.21,5.39),P=0.014,分别]。此外,TrPS(CD8)和TrPS(CD4)与CMV和CAFs呈负相关。这些发现加深了我们对化疗的免疫调节作用的理解,并强调化疗后Tregs的空间景观变化应考虑到个性化免疫治疗。旨在最终改善NSCLC患者的临床预后。
It is crucial to decipher the modulation of regulatory T cells (Tregs) in tumor microenvironment (TME) induced by chemotherapy, which may contribute to improving the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer (NSCLC). We retrospectively collected specimens from patients with II-III NSCLC, constituting two cohorts: a neoadjuvant chemotherapy (NAC) cohort (N = 141) with biopsy (N = 58) and postoperative specimens (N = 141), and a surgery-only cohort (N = 122) as the control group. Then, the cell density (Dens), infiltration score (InS), and Treg-cell proximity score (TrPS) were conducted using a panel of multiplex fluorescence staining (Foxp3, CD4, CD8, CK, CD31, ɑSMA). Subsequently, the association of Tregs with cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) was analyzed. Patients with NAC treatment have a higher density of Tregs in both paired (P < 0.001) and unpaired analysis (P = 0.022). Additionally, patients with NAC treatment showed higher infiltration score (paired, P < 0.001; unpaired, P = 0.014) and more CD8+T cells around Tregs (paired/unpaired, both P < 0.001). Subgroup analysis indicated that tumors with a diameter of ≤ 5 cm exhibited increase in both Dens(Treg) and InS(Treg), and gemcitabine, pemetrexed and taxel enhanced Dens(Treg) and TrPS(CD8) following NAC. Multivariate analysis identified that the Dens(Tregs), InS(Tregs) and TrPS(CD8) were significantly associated with better chemotherapy response [OR = 8.54, 95%CI (1.69, 43.14), P = 0.009; OR = 7.14, 95%CI (1.70, 30.08), P = 0.024; OR = 5.50, 95%CI (1.09, 27.75), P = 0.039, respectively] and positive recurrence-free survival [HR = 3.23, 95%CI (1.47, 7.10), P = 0.004; HR = 2.70; 95%CI (1.27, 5.72); P = 0.010; HR = 2.55, 95%CI (1.21, 5.39), P = 0.014, respectively]. Moreover, TrPS(CD8) and TrPS(CD4) were negatively correlated with the CMVs and CAFs. These discoveries have deepened our comprehension of the immune-modulating impact of chemotherapy and underscored that the modified spatial landscape of Tregs after chemotherapy should be taken into account for personalized immunotherapy, aiming to ultimately improve clinical outcomes in patients with NSCLC.