Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

Abstract

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and "educate" (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

Keywords: Hodgkin lymphoma; immune escape; tumor microenvironment; tumor-associated macrophages.

Figure 1

Education of normal cells in the tumor microenvironment of classic Hodgkin lymphoma. (1) Hodgkin and Reed–Sternberg (HRS) cells, by secreting transforming growth factor β (TGF-β), interleukin (IL)-13, macrophage colony-stimulating factor (M-CSF) and lactic acid, educate monocytes or tumor-associated macrophages (TAMs) to become immunosuppressive M2-TAMs (programmed death-ligand 1, PD-L1⁺; and indoleamine 2,3-dioxygenase, IDO⁺). (2) M2-TAMs, by secreting TGF-β, IL-10, C-C motif chemokine ligand (CCL) 17 and CCL22 and by expressing PD-L1 and IDO, induce exhaustion of programmed cell death protein 1 (PD-1)⁺ effector T and NK cells. (3) HRS cells, by secreting TGF-β, galectin-1 (GAL-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and prostaglandin (PG-E), induce the differentiation of CD4⁺ T cells towards regulatory T cells (Tregs) (forkhead box P3, FoxP3⁺). (4) High levels of extracellular adenosine (eADO) in the TME inhibit T effector cell activity. (5) Extracellular vesicles (EVs) secreted by HRS cells convert fibroblasts to α smooth muscle actin (αSMA)⁺ cancer-associated fibroblasts (CAFs) that secrete IL-1α, IL-6, tumor necrosis factor (TNF-α), M-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF). (6) The mature, bioactive form of A Disintegrin And Metalloproteinase (ADAM10) is released in exosome-like vesicles (ExoV) by HRS cells and lymph node mesenchymal stromal cells (MSCs). Diffusion of ADAM10 activity due to ExoV results in the release of TNF-α, MHC class I chain-related a (sMICA), and soluble sCD30 that may interfere with host immune surveillance, immunotherapy or brentuximab vedotin activity. (7) HRS cells induce MSC growth and educate MSCs to secrete CCL5. Tumor-educated MSCs (E-MSCs), through the secretion of CCL5, recruit monocytes. CTLA4, cytotoxic T lymphocyte antigen 4; STAT3/6, signal transducer and activator of transcription.

Figure 2

Mechanism of action of the checkpoint inhibitors nivolumab and pembrolizumab, and the tryptophan mimetic indoximod. (A) Anti-programmed death-1 (PD-1) antibodies. The anti-PD-1 antibodies (nivolumab and pembrolizumab) (1) inhibit the engagement of PD-1⁺ T cells by PD-L1⁺ Hodgkin and Reed–Sternberg (HRS) cells or PD-L1⁺ M2-tumor-associated macrophages (TAMs), (2) thus counteracting T and natural killer (NK) cell exhaustion due to PD-1/PD-L1 interactions. (B) Indoximod. (1) Indoleamine 2,3-dioxygenase (IDO) converts tryptophan (Trp) to kynurenine (Kyn). In classic Hodgkin lymphoma (cHL), indoximod, acting as a Trp mimetic, may inhibit the polarization of effector CD4⁺ T cells towards Tregs due to increased levels of kynurenine. (2) Indoximod may counteract anergy or exhaustion of effector CD4⁺ T cells due to kynurenine. Chr 9p, chromosome 9 petit; Teff, effector T cell.

Figure 3

Proposed mechanism for the inhibitory effects of maraviroc, RP6530, chimeric antigen receptor T cells (CART)123, trabectedin and zoledronic acid on tumor cells and the tumor microenvironment (TME). (A) Maraviroc. (1) The C-C chemokine receptor type 5 (CCR5) antagonist maraviroc inhibits the recruitment of both monocytes and mesenchymal stromal cells (MSCs) by classic Hodgkin lymphoma (cHL) cells. (2) The education of MSCs cells (E-MSCs) induces the secretion of C-C motif ligand 5 (CCL5) (red dots). (3) Maraviroc inhibits the recruitment of monocytes by CCL5 secreted by E-MSCs. (4) Maraviroc inhibits cHL clonogenic growth promoted by CCR5 ligands (green dots) secreted by tumor-educated monocytes (E-monocytes) and E-MSCs (CCL5+). (5) Maraviroc decreases cHL tumor xenograft growth and monocyte infiltration. (B) RP6530, a PI3K-δ/γ inhibitor. (1) RP6530 inhibits Hodgkin and Reed–Sternberg (HRS) cell growth (2) and lactate acid production and secretion. (3) RP630 treatment of HRS cells inhibits their ability to maintain tumor-associated macrophage (TAM)-M2 immunosuppressive polarization. (4) RP6530 repolarizes M2-TAMs towards M1-TAMs. (5) RP6530 decreases cHL tumor xenograft growth and M2-TAM reprogramming. (C) CART123. (1) Anti-CD123-CART cells kill CD123⁺ HRS cells and (2) CD123⁺ M2-TAMs. (3) Anti-CD123-CART cells exert potent effector function against Hodgkin lymphoma in vivo. (D) Trabectedin and zoledronic acid. (1) Trabectedin and zoledronic acid may kill HRS cells, (2) monocytes and TAMs. (3) Trabectedin and zoledronic acid may decrease the secretion of inflammatory and angiogenic factors by tumor cells or the TME. PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase isozymes M2.