Somatostatin Receptor 2: A Potential Predictive Biomarker for Immune Checkpoint Inhibitor Treatment

Abstract

Somatostatin receptor 2 (SSTR2), the most abundant receptor of somatostatin (SST), possesses immunoreactivity and is altered in many cancers. However, the association between SSTR2 and efficacy of immune checkpoint inhibitors (ICIs) has not yet been reported. Immunohistochemistry (IHC) information across 20 cancers was collected from the Human Protein Atlas (HPA) and used to analyze the expression of SSTR2. Immune signatures collected from public databases, such as BioCarta or Reactome, were used to investigate the association between SSTR2 and the tumor microenviroment in the Cancer Genome Atlas (TCGA). Data from cohorts treated with ICIs were collected to assess whether SSTR2 is associated with benefits from ICIs treatment. In the HPA, we found the SSTR2 IHC-positive rate of 13 cancers to be above 50%. Five types of cancer express SSTR2 mildly (positive rate: 25%-50%), while the remaining two types of cancer barely stained SSTR2-positive (positive rate: 0%-24%). In TCGA analysis, immune cell signatures and immune function pathways were enriched in high SSTR2 expression groups in most cancers. In each ICIs treated cohort, patients with high SSTR2 expression experienced numerically superior objective response rate (Braun: 14.8% vs 13.4%, p = 0.85; Gide: 69.4% vs 40.5%, p = 0.025; Mariathasan: 22.4% vs 16.7%, p = 0.233; Miao: 37.5% vs 11.8%; Riaz: 32.0% vs 7.7%, p = 0.067) and overall survival (Braun: HR (95%CI): 0.80 [0.62-1.04], p = 0.80; Gide: HR (95%CI): 0.61 [0.29-1.30], p = 0.20; Mariathasan: HR (95%CI): 0.83 [0.64-1.08], p = 0.16; Miao: HR (95%CI): 0.24 [0.086-0.65], p = 0.0028; Nathanson cohort: HR (95%CI): 0 [0-inf], p = 0.18; Riaz: HR (95%CI): 0.24 [0.086-0.65], p = 0.028) than patients with low SSTR2 expression. In pooled cohort, we found these differences were significant (Pool: 24.6% vs 16.7%, p = 0.0077; HR (95% CI): 0.77 [0.65-0.91], p = 0.0018). Our results suggest that SSTR2 is a potential predictive biomarker for response to ICIs.

Keywords: bioinformatics; immune checkpoint inhibitors; predictive biomarker; somatostatin receptor 2; tumor microenvironment.

FIGURE 1

Expression of SSTR2 across 20 cancers in the human protein atlas. (A) The summary graph of the SSTR2 immunohistochemistry (IHC) positive rate in the human protein atlas. (B) The SSTR2 IHC results of 20 cancers.

FIGURE 2

Immune signatures compared between the SSTR2-high group and SSTR2-low group. (A–H) Immune cell signatures in SSTR2-high and SSTR2-low groups. (I–O) Immune functional pathway signatures in SSTR2-high and SSTR2-low groups. The square point Y-axis positions were the scores median of SSTR2-high group, X-axis positions were the scores median of SSTR2-low group. Bars show 25%–75% scores range of different groups in each cancer.

FIGURE 3

Immune signature enrichment results and correlation between SSTR2 expression and immune signatures scores. (A–D) immune signatures enrichment plots in TCGA pooled Q18 cohort. (E–H) Correlation summary plots of SSTR2 expression and immune signature scores.

FIGURE 4

Survival analysis between SSTR2-high groups and SSTR2-low groups in ICIs treated cohorts. (A,B) Histogram describing objective response rate and responder percentage. (C–I) Kaplan-Meier curves of overall survival (OS) in ICIs treated cohorts comparing patients with high and low SSTR2 expression.