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

Locatelli, Silvia L.; Careddu, Giuseppa; Serio, Simone; Consonni, Francesca Maria; Maeda, Akihiro; Viswanadha, Srikant; Vakkalanka, Swaroop; Castagna, Luca; Santoro, Armando; Allavena, Paola; Sica, Antonio; Carlo‐Stella, Carmelo

doi:10.1158/1078-0432.ccr-18-1133

Cited by 68 publications

(75 citation statements)

References 49 publications

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“…S1B). This suggests, in contrast to previous findings (Locatelli et al, 2018;Ruella et al, 2017), that attraction and differentiation are distinct processes regulated by different cytokines or chemokines.…”

Section: Hodgkin Lymphoma Cell Supernatants Attract Monocytes and Inicontrasting

confidence: 99%

“…Preliminary data show the additional involvement of BTK‐ and PI3K‐regulated pathways, as respective inhibitors affect both M‐CSF‐ and L428‐CM‐mediated Mφ differentiation. This supports the recent observation of a preclinical model that used RP6530 to target the interaction between HL cells and Mφ (Locatelli et al , ). We propose that M‐CSF induces a network of signaling pathways to activate autocrine Mφ differentiation factors, whereas IL13 directly promotes an early differentiation program.…”

Section: Discussionsupporting

confidence: 89%

“…We present a combined analysis of transcriptome and proteome data to compare lymphoma-educated to M-CSF-differentiated Mφ. We extend recent data and models, which have proposed CXCL13, CCL5, and M-CSF as central players in the interaction of HL cells with Mφ (Carey et al, 2017;Casagrande et al, 2019;Ford et al, 2015;Locatelli et al, 2018;Ruella et al, 2017;Scott and Steidl, 2014;Tudor et al, 2014). We demonstrate that Jak/STAT signaling and, especially, IL13 are involved in the regulation of the expression of MRC1 and the abundance of CD206 on the surface of HL-educated Mφ.…”

Section: Discussionsupporting

confidence: 82%

“…Inhibition of the Jak/STAT pathway targets not only lymphoma cells directly, but may also affect lymphoma-educated Mφ development and/or activity. This supports the simultaneous targeting of both lymphoma cells and Mφ with PI3K inhibitors, and the use of Maraviroc for the blocking of CCR5 in these cells (Casagrande et al, 2019;Locatelli et al, 2018). In line with this, targeting the pattern recognition receptor MARCO can alter Mφ polarization and result in reduced tumor growth (Georgoudaki et al, 2016).…”

Section: Discussionsupporting

confidence: 55%

“…Additionally, Mφ are an integral part of the TME, and the number of CD68-positive Mφ predicts the patient's outcome (Scott and Steidl, 2014). Therefore, targeting the interaction between HL cells and Mφ presents a promising strategy in the treatment of HL (Locatelli et al, 2018;Ruella et al, 2017). However, our knowledge of the functions and interactions of Mφ in HL is still limited (Mantovani et al, 2002;Martinez and Gordon, 2014;Steidl et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

et al. 2020

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Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma‐promoting, alternatively activated M2‐like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor‐associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)‐conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B‐cell lymphoma (DLBCL) cells or, classically, by macrophage colony‐stimulating factor (M‐CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD‐L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M‐CSF stimulation in M2‐like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose‐dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL‐TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co‐cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma‐only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206‐positive cells, with high MRC1 expression being characteristic of HL‐stage IV. In summary, the lymphoma‐TAM interaction contributes to matrix‐remodeling and lymphoma cell dissemination.

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Section: Hodgkin Lymphoma Cell Supernatants Attract Monocytes and Inicontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

et al. 2020

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Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

Kun

Cai

Zhu

et al. 2022

Cancer Communications

165

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Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression, and targeting TAMs has become one of the most favored immunotherapy strategies. In addition, macrophages and liver cancer cells have distinct origins. At the early stage of liver cancer, macrophages can provide a niche for the maintenance of liver cancer stem cells. In contrast, cancer stem cells (CSCs) or poorly differentiated tumor cells are key factors modulating macrophage activation. In the present review, we first propose the origin connection between precursor macrophages and liver cancer cells. Macrophages undergo dynamic phenotypic transition during carcinogenesis. In this course of such transition, it is critical to determine the appropriate timing for therapy and block specific markers to suppress pro‐tumoral TAMs. The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews. Complex crosstalk occurs between TAMs and liver cancer cells. TAMs play indispensable roles in tumor progression, angiogenesis, and autophagy due to their heterogeneity and robust plasticity. In addition, macrophages in the TME interact with other immune cells by directing cell‐to‐cell contact or secreting various effector molecules. Similarly, tumor cells combined with other immune cells can drive macrophage recruitment and polarization. Despite the latest achievements and the advancements in treatment strategies following TAMs studies, comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking. In this review, we discussed the interactions between TAMs and liver cancer cells (from cell origin to maturation), the latest therapeutic strategies (including chimeric antigen receptor macrophages), and critical clinical trials for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.

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Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

Bai,

Sun,

Lei

et al. 2023

Drug Development Research

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The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2‐d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU‐DHL‐6 cells (IC50 = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration‐dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

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

Cited by 68 publications

References 49 publications

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

Discovery of novel pyrido[3,2‐d]pyrimidine derivatives as selective and potent PI3Kδ inhibitors

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