Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 3, Pages 1098-1112Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-1133
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Funding
- Italian Association for Cancer Research, Milan, Italy (AIRC) [20575]
- Fondazione Regionale Ricerca Biomedica, Milan, Italy (FRRB project) [2015-0042]
- Worldwide Cancer Research, UK [15-1346]
- Ministero dell'Istruzione dell'Universita e della Ricerca (MIUR), Milan, Italy (PRIN) [C52F16000940001]
- Irish Research Council 2017, Ireland (IRC) [19885]
- Marie Skoodowska Curie Individual European Fellowship-H2020-MSCA-IF-2015-EF-ST [706557]
- Marie Curie Actions (MSCA) [706557] Funding Source: Marie Curie Actions (MSCA)
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Purpose: 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 d and g isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kd/g inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Experimental Design: 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. Results: 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 PI3Kd/g-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%). Conclusions: Our results support PI3Kd/g inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.
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