Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

Abstract

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia‐inducible factor 2 (HIF2)‐mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death‐ligand 1 (PD‐L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD‐L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD‐L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD‐L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD‐L1 and CD8 expression was lower in norepinephrine than epinephrine‐secreting PPGL. This in silico analysis also revealed the low PD‐L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α‐coding gene, EPAS1, which, together with SDH‐mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Genetic variants in hypoxia‐inducible factor pathway are associated with colorectal cancer risk and immune infiltration

“…Hypoxia is related to the immune status of tumour cells. EPAS1 plays a valuable role in predicting the outcome of PD‐L1 treatment 9 . SNP rs34533650 influences EPAS1 expression in an allele‐specific manner, and EPAS1 expression was associated with the infiltration levels of macrophages, 44 suggesting that genetic variants may influence immune infiltration through the expression of EPAS1 gene associated with colorectal cancer risk.…”

“…8 Hypoxia activates several adaptive responses, which are mainly mediated by HIF1α and HIF2α. 9 Previous studies suggested that hypoxia-induced changes affect tumour immune microenvironment. 10 Hypoxia-inducible factor (HIF) pathway genes influence the expression of gene in both tumour cells and immune cells and affect tumour progression and treatment response.…”

“…Hypoxia activates several adaptive responses, which are mainly mediated by HIF1α and HIF2α 9 . Previous studies suggested that hypoxia‐induced changes affect tumour immune microenvironment 10 .…”

“…EPAS1 encodes a subunit of HIFs 15 and shows multifaceted effects, including regulation of angiogenesis, haemoglobin concentration and erythrocytosis 16 . EPAS1 affect immune infiltration in paraganglioma and pheochromocytoma 9 . The immune microenvironment can be used to predict the treatment outcomes and curative effects, 17 and the treatment response and prognosis of colorectal cancer are associated with the immune microenvironment 18 .…”

“… 16 EPAS1 affect immune infiltration in paraganglioma and pheochromocytoma. 9 The immune microenvironment can be used to predict the treatment outcomes and curative effects, 17 and the treatment response and prognosis of colorectal cancer are associated with the immune microenvironment. 18 In addition, the outcome and progression of many types of diseases are affected by single nucleotide polymorphisms (SNPs), 19 and studies have demonstrated that SNPs in HIF‐1α are associated with susceptibility to multiple cancers.…”