The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues and extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

Keywords: cancer immunotherapy; immune system; neuroendocrine tumors; paraganglioma; perspectives; pheochromocytoma.

Graphical Abstract

Figure 1.

Simplified cancer immunoediting process. Cancer immunoediting proceeds through the phases of elimination, equilibrium, and escape. During the elimination phase the innate and adaptive immune system can recognize MHC expression and antigens of tumor cells and eliminate them. If cancer cells survive the elimination phase, they progress into equilibrium phase where immune pressure select low-immunogenic tumor cell clones. Subsequently, the edited tumor cells can escape from immune surveillance. In this escape phase, tumors are clinically detectable. Tumor cells promote an immunosuppressive microenvironment by recruiting immune regulatory cells, altering immune cell trafficking, dysregulating the secretion of signaling molecules and metabolites, and upregulating surface molecules. Abbreviations: DC, dendritic cell; IL, interleukin; INF, interferon; MHC, major histocompatibility complex; NK cells, natural killer cells; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophage; TME, tumor microenvironment; TGF, tumor growth factor; Treg, T regulatory cells.

Figure 2.

Classification of immune subtypes within genomic cluster. The proportion (%) of samples of each immune subtype per genomic cluster is shown (x-axis). Data have been extracted from Ghosal et al (20) (first graphs column: Immunecluster1, M2 macrophages; Immunecluster2, monocytes; Immunecluster3, activated NK cells; Immunecluster4, Tregs and M0 macrophages; Immunecluster5, CD8+ and CD4+ T cells) and Calsina et al (21) (second and third graph column: D, depleted; F, fibrotic; IE, immune-enriched, nonfibrotic; IE/F, immune-enriched, fibrotic; C3, inflammatory; C4, lymphocyte depleted; C5, immunologically quiet).

Figure 3.

Examples of targets of immune system and TME for PET imaging. Abbreviations: Ara-G, arabinosylguanine; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FAP, fibroblast activation protein; IL2-R, interleukin-2 receptor; LAG-3, lymphocyte activation gene 3; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; TSPO, translocator protein.

Figure 4.

Intratumoral immunotherapy. (A) Advantages and disadvantages of intratumoral and systemic administration of immunotherapy. (B) Mechanism of MBTA immunotherapy (preclinical study). (1) MBTA therapy is consisted of mannan-BAM, 3 TLR ligands, and anti-CD40 antibody. After intratumoral application of MBTA therapy, mannan-BAM is nonspecifically anchored to lipid bilayer of tumor cells. (2) TLR ligands recruit the immune cells into the tumor. Opsonized tumor cells are then recognized by infiltrated innate immune cells and killed, resulting in (3) the release of antigens which can be present in lymphatic nodes and activate adaptive immune cells. The anti-CD40 antibody binds to CD40 receptor, which mainly expressed on APCs and initiates their activation. (4) Adaptive immune cells, mostly CD4+ and CD8+ T cells, then infiltrate the tumor and kill tumor cells. Abbreviations: DCs, dendritic cells; NK cells, natural killer cells; TLR, toll-like receptor.

Figure 5.

Enhancing the antitumor efficacy of immunotherapy with immune-supportive therapies. Variety of immunotherapies can be effective in targeting PPGL. To maximize the benefits of immunotherapy, combination of more immunotherapies, different delivery routes (eg, systemic vs intratumoral), and supportive therapies that target hostile TME may be selected to enhance the effective elimination of tumor cells by immune system. #Currently in clinical trials or clinical use for cancer treatment (status to date December 1, 2023, clinicaltrials.gov). *Therapies in the clinical use or trial for PPGL. Abbreviations: IL, interleukin; IFN, interferon; poly(ICLC), derivate of polyinosinic:polycytidylic acid; CpG, cytosine-phosphorothioate-guanine oligodeoxynucleotides; LTA, lipoteichoic acid; DC, dendritic cell; TLR, Toll-like receptor; CAR-T cell, chimeric antigen receptor T cells; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; LAG-3, lymphocyte-activation gene 3; TIGIT, T-Cell immunoreceptor with Ig and ITIM domains; HIF, hypoxia-inducible factor; TKI, tyrosine-kinase inhibitors; VEGF, vascular endothelial growth factor; SUCNR1, succinate receptor 1; IDO, indoleamine 2,3-dioxygenase; MIBG, metaiodobenzylguanidine.