Abstract：
OBJECTIVE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly.
METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics.
RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma.
CONCLUSIONS: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.
METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics.
RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma.
CONCLUSIONS: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.
摘要：
目的：预测肢端肥大症患者对第一代生长抑素受体配体（fg-SRL）的耐药性仍然是一个很大的挑战。肿瘤相关免疫成分参与各种病理过程,包括耐药性。我们旨在鉴定与fg-SRL抗性有关的免疫成分，并研究可靶向治疗这些耐药肢端肥大症的生物标志物。
方法：我们进行了一项回顾性研究，包括35例肢端肥大症患者，这些患者在术后接受fg-SRL治疗。收集临床病理数据，SSTR2表达式，和免疫学特征，我们利用单变量，二元逻辑回归，和ROC分析，以评估它们在fg-SRL耐药中的预测作用。Spearman相关分析进一步检查了感兴趣特征之间的相互作用。
结果：19例患者（54.29%）表现出对术后fg-SRL的抵抗。诊断时的GH水平，术前肿瘤体积,T2WI-MRI强度,粒度,PD-L1、SSTR2和CD8+T细胞浸润显示与fg-SRL的临床结果相关。值得注意的是,T2WI-MRI高强度,PD-L1-IRS>7，CD8+T细胞浸润<14.8/HPF，SSTR2-IRS<5.4是fg-SRL抗性的可靠预测因子。相关分析显示PD-L1表达与CD8+T细胞浸润呈负相关,同时显示与生长激素瘤的术前肿瘤体积呈正相关。此外,5例fg-SRL抵抗患者接受了再次手术。fg-SRL处理后，观察到PD-L1和SSTR5表达显着增加，而SSTR2在生长激素瘤中的表达降低。
结论：PD-L1表达和CD8+T细胞浸润，独立或与SSTR2表达和T2WI-MRI强度结合，可以形成一个预测模型，指导fg-SRL就业的临床决策。此外，通过免疫疗法靶向PD-L1并采用对SSTR5具有更高亲和力的第二代SRL是解决生长激素瘤中fg-SRL耐药的有前景的策略.
方法：我们进行了一项回顾性研究，包括35例肢端肥大症患者，这些患者在术后接受fg-SRL治疗。收集临床病理数据，SSTR2表达式，和免疫学特征，我们利用单变量，二元逻辑回归，和ROC分析，以评估它们在fg-SRL耐药中的预测作用。Spearman相关分析进一步检查了感兴趣特征之间的相互作用。
结果：19例患者（54.29%）表现出对术后fg-SRL的抵抗。诊断时的GH水平，术前肿瘤体积,T2WI-MRI强度,粒度,PD-L1、SSTR2和CD8+T细胞浸润显示与fg-SRL的临床结果相关。值得注意的是,T2WI-MRI高强度,PD-L1-IRS>7，CD8+T细胞浸润<14.8/HPF，SSTR2-IRS<5.4是fg-SRL抗性的可靠预测因子。相关分析显示PD-L1表达与CD8+T细胞浸润呈负相关,同时显示与生长激素瘤的术前肿瘤体积呈正相关。此外,5例fg-SRL抵抗患者接受了再次手术。fg-SRL处理后，观察到PD-L1和SSTR5表达显着增加，而SSTR2在生长激素瘤中的表达降低。
结论：PD-L1表达和CD8+T细胞浸润，独立或与SSTR2表达和T2WI-MRI强度结合，可以形成一个预测模型，指导fg-SRL就业的临床决策。此外，通过免疫疗法靶向PD-L1并采用对SSTR5具有更高亲和力的第二代SRL是解决生长激素瘤中fg-SRL耐药的有前景的策略.
