Abstract
Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%-76%). Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.
Highlights
Primary refractory and early-relapsed patients with Hodgkin lymphoma experience poor responses to salvage chemotherapy and dismal long-term disease control [1,2,3]
Idelalisib is the first PI3Kd inhibitor to be approved for follicular lymphoma and chronic lymphocytic leukemia [11, 12], and we previously reported that PI3Kd isoform inhibition results in direct Hodgkin lymphoma cell killing [13]
The PI3K/Akt pathway is consistently activated in Hodgkin lymphoma [24]
Summary
Primary refractory and early-relapsed patients with Hodgkin lymphoma experience poor responses to salvage chemotherapy and dismal long-term disease control [1,2,3]. The d isoform of PI3K is highly expressed in tissues of hematopoietic origin and is involved in the activation, proliferation, survival, homing, and retention of B-cells in lymphoid tissues [10]. The PI3Kg isoform, highly expressed in leukocytes, may play a more crucial role in the immune system than that in oncogenesis [10]. Much effort has been devoted to PI3Kg as a target in inflammatory diseases driven by leukocytes [14]. Inflammation driven by tumor-associated macrophages (TAMs) is considered a hallmark of cancer, contributing to both cancer cell expansion and angiogenesis [15]. Recent data in solid tumors show that selectively targeting the g isoform of PI3K in TAMs modulates the immunosuppressive tumor microenvironment (TME), resulting in tumor regression [16,17,18]
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