Tumor-infiltrating immune cells predict the response to somatostatin receptor ligands only in somatotropinomas naïve to medical therapy.

Tumor-infiltrating immune cells (TICs) are important components of the tumor microenvironment (TME). They regulate somatotroph adenoma treatment responses to therapy with somatostatin receptor ligands (SRLs), mediated by soluble factors and cytokines. In this study, we assessed the effect of SRLs treatment on TICs. A retrospective and observational study was performed on acromegaly patients to compare the number of TICs in 75 patients naïve to SRL before surgery and in 33 patients treated with SRL for at least 6 months before surgery. In SRLs-naive patients at surgery, the CD68+/CD8+ ratio was higher in invasive tumors (4.9, IQR: 14, p = .028) than in non-invasive tumors (4.3, IQR: 4.2) as well as in patients not responsive to post-surgical/adjuvant treatment with SRLs (7.5, IQR: 13, p = .006) than those responsive to treatment (3.4, IQR: 3.2). In patients treated with SRLs before surgery, the number of CD68+ macrophages and the ratio CD68+/CD8+ were lower in patients non-responsive to post-surgery/adjuvant SRL treatment (CD68+: 48/HPFs, IQR: 22.9, p = .005; CD68+/CD8+: 2.0, IQR: 3.6, p = .05) than in responsive patients (CD68+: 80/HFPs, IQR: 51, CD68+/CD8+: 5, IQR: 5.6). Higher CD68+/CD8+ ratio was an independent risk factor for post-surgery SRL treatment resistance, only in patients naïve to SRLs at surgery (OR: 4.3, 95% IC: 1.4-12.9, p = .006). Our results indicate a presurgical SRL therapy interplay with TICs in somatotroph adenomas and show that the CD68+/CD8+ ratio is a biomarker for treatment resistance in SRL-naïve patients. CLINICAL TRIAL REGISTRATION: The Clinical Trial Registration number is 5116.