journal contribution
posted on 2023-03-31, 20:23 authored by Silvia L. Locatelli, Giuseppa Careddu, Simone Serio, Francesca M. Consonni, Akihiro Maeda, Srikant Viswanadha, Swaroop Vakkalanka, Luca Castagna, Armando Santoro, Paola Allavena, Antonio Sica, Carmelo Carlo-Stella Supplementary Fig. S1. Constitutive activation of the PI3K/Akt pathway in Hodgkin lymphoma patients and cell lines. Supplementary Fig. 2. Profiling of RP6530 target genes and related enriched pathways. Supplementary Fig. S3. Relevant KEGG pathway in GSEA preranked analysis of RP6530- modulated genes. Supplementary Fig. S4. Relevant PID pathway in GSEA preranked analysis of RP6530- modulated genes. Supplementary Fig. S5. RP6530 inhibits tumor glycolysis and HIF1ð�›, pathways. Supplementary Fig. S6. Validation of PKM2 inhibition in HL cell lines treated with RP6530. Supplementary Fig. S7. RP6530 induced cell death in M1 and M2 stimulated macrophages. Supplementary Fig. S8. PKM2-dependent macrophage class switch. Supplementary Fig. 9. RP6530 modulates TAMs polarization in HL xenografts. Supplementary Fig. S10. RP6530 induces tumor vasculature disruption.
Funding
Italian Association for Cancer Research, Milan, Italy
Fondazione Regionale Ricerca Biomedica, Milan, Italy
Worldwide Cancer Research, UK
History
ARTICLE 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.
