Immunohistochemical profiling of HIF-2[alpha] and SSTR2 with the tumor microenvironment in metastatic pheochromocytoma and paraganglioma

Masaki Uchihara; Akiyo Tanabe; Yuki Kojima; Tatsunori Shimoi; Akiko Maeshima; Kotaro Umamoto; Eijiro Nakamura; Akihiko Shimomura; Chikako Shimizu; Kan Yonemori; Hiroshi Kajio

doi:10.1530/endoabs.99.P310

P310

Prev Next

Section Contents Cite

Endocrine Abstracts (2024) 99 P310 | DOI: 10.1530/endoabs.99.P310

ECE2024 Poster Presentations Endocrine-Related Cancer (40 abstracts)

Immunohistochemical profiling of HIF-2α and SSTR2 with the tumor microenvironment in metastatic pheochromocytoma and paraganglioma

Masaki Uchihara ^1,2 , Akiyo Tanabe ¹ , Yuki Kojima ² , Tatsunori Shimoi ² , Akiko Maeshima ² , Kotaro Umamoto ¹ , Eijiro Nakamura ² , Akihiko Shimomura ¹ , Chikako Shimizu ¹ , Kan Yonemori ² & Hiroshi Kajio ¹

View

Author affiliations

¹National Center for Global Health and Medicine; ²National Cancer Center Hospital

Introduction: Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. Immunotherapy, a breakthrough in oncology, is effective in some cases of PPGLs; however, the response rate remains limited. Therefore, one strategy to improve immunotherapy is combining drugs with different action mechanisms and target resistance. The association between the tumor microenvironment (TME), including tumor-associated macrophages (TAMs) with hypoxia-induced factor-2α (HIF-2α) and somatostatin receptor 2 (SSTR2) in PPGLs, is critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored.

Methods: We analyzed the expression of HIF-2α, SSTR2A, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), TAMs (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. We also evaluated the association between these biomarkers, the prognosis, and the response to systemic chemotherapy.

Results: Among 45 patients with PPGLs, HIF2α and SSTR2A were positively expressed in 14 (31.1%) and 21 (46.7%) patients, respectively. 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 TAMs) and SSTR2A expression (r=−0.385, P=0.006), with a stronger correlation in metastatic cases (r=−0.535, P=0.009). HIF-2α expression positively correlated with PD-L1 IHS (r=−0.348, P=0.013). The co-expression of PD-L1 (IHS>10) and HIF-2α was found in seven patients (15.6%). In light of the negative correlation between SSTR2A and the CD163/CD68 ratio, our analysis assessed the time of tumor progression across the four groups based on these parameters. All 11 patients in the low CD163/CD68 ratio and the negative expression of the SSTR2A group showed no progression or detection of metastasis. No association was observed between HIF-2α positivity, CD163/CD68 ratio, and response to CVD chemotherapy.

Conclusion: We found a negative association between M2 polarization TAMs and SSTR2A expression in PPGLs. We also observed a relationship between high PD-L1 expression and increased HIF-2α expression. Our data provides the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.