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. 2024 Jun 11;16(12):2191.
doi: 10.3390/cancers16122191.

Immunohistochemical Profiling of SSTR2 and HIF-2α with the Tumor Microenvironment in Pheochromocytoma and Paraganglioma

Masaki Uchihara  1   2   3 , Akiyo Tanabe  1 , Yuki Kojima  4 , Tatsunori Shimoi  4 , Akiko Miyagi Maeshima  5 , Kotaro Umamoto  1   3 , Akihiko Shimomura  2   6 , Chikako Shimizu  2   6 , Yuto Yamazaki  7 , Eijiro Nakamura  4   8 , Yoshiyuki Matsui  8 , Nobuyuki Takemura  9 , Hideyo Miyazaki  10 , Kazuki Sudo  4 , Kan Yonemori  4 , Hiroshi Kajio  1
Affiliations

Immunohistochemical Profiling of SSTR2 and HIF-2α with the Tumor Microenvironment in Pheochromocytoma and Paraganglioma

Masaki Uchihara et al. Cancers (Basel). .

Abstract

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, p = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, p = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.

Keywords: HIF2α; immunotherapy; paraganglioma; pheochromocytoma; somatostatin receptor; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative immunohistochemistry staining images of SSTR2A and HIF-2α in PPGLs (Magnification: ×400). The immunoreactivity of SSTR2A was evaluated based on Volante scores. For statistical analysis, SSTR2A scores of 0 and 1 were considered negative, while 2 and 3 were considered positive. HIF-2α was evaluated for both the tumor cell nucleus and cytoplasm. Abbreviations: SSTR2A, somatostatin receptor 2A; HIF, hypoxia-induced factor.
Figure 2
Figure 2
Correlation matrix of SSTR2A and HIF-2α with tumor microenvironment in PPGLs. (A) All patients (n = 45). (B) Metastatic cases (n = 18). Abbreviations: SSTR2A, somatostatin receptor 2A; HIF, hypoxia-induced factor; NUC, nuclear.
Figure 3
Figure 3
(A) Scatterplot showing a positive correlation between SSTR2A expression and CD163/CD68 ratio. The horizontal bars indicate the median CD163/CD68 ratio for each SSTR2A score in metastatic and non-metastatic PPGLs. (B) The time to progression analyses according to CD163/CD68 ratio and SSTR2A expression in patients with PPGLs. Abbreviations: SSTR2A, somatostatin receptor 2A.
See this image and copyright information in PMC

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