Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

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

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Abstract

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 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.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 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%).Conclusions: 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.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusE-pub ahead of print - Oct 23 2018

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Cellular Microenvironment
Tumor Microenvironment
Hodgkin Disease
Phosphatidylinositol 3-Kinases
Macrophages
Neoplasms
Reed-Sternberg Cells
Immunosuppressive Agents
Heterografts
Chemokine CCL17
RNA Sequence Analysis
Phenotype
Cell Line
Pyruvate Kinase
Macrophage Activation
Glycolysis
Lactic Acid
Protein Isoforms
Research Design
Down-Regulation

Cite this

@article{cf97ec795e9b46d09e32b62b9db7ba80,
title = "Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530",
abstract = "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 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.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 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{\%}).Conclusions: 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.",
author = "Locatelli, {Silvia L} and Giuseppa Careddu and Simone Serio and Consonni, {Francesca M} and Akihiro Maeda and Srikant Viswanadha and Swaroop Vakkalanka and Luca Castagna and Armando Santoro and Paola Allavena and Antonio Sica and Carmelo Carlo-Stella",
note = "{\circledC}2018 American Association for Cancer Research.",
year = "2018",
month = "10",
day = "23",
doi = "10.1158/1078-0432.CCR-18-1133",
language = "English",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",

}

TY - JOUR

T1 - Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

AU - Locatelli, Silvia L

AU - Careddu, Giuseppa

AU - Serio, Simone

AU - Consonni, Francesca M

AU - Maeda, Akihiro

AU - Viswanadha, Srikant

AU - Vakkalanka, Swaroop

AU - Castagna, Luca

AU - Santoro, Armando

AU - Allavena, Paola

AU - Sica, Antonio

AU - Carlo-Stella, Carmelo

N1 - ©2018 American Association for Cancer Research.

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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 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.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 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%).Conclusions: 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.

AB - 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 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.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 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%).Conclusions: 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.

U2 - 10.1158/1078-0432.CCR-18-1133

DO - 10.1158/1078-0432.CCR-18-1133

M3 - Article

C2 - 30352904

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -