Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia

Patrussi, Laura; Capitani, Nagaja; Baldari, Cosima T.

doi:10.3390/cancers13246301

Cited by 10 publications

(8 citation statements)

References 106 publications

(164 reference statements)

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“…We have previously reported that leukemic cells from CLL patients shape the lymphoid microenvironment to promote their survival while suppressing anti-cancer immunity through both contact-dependent and contact-independent interactions (Patrussi et al, 2021; Boncompagni et al, 2024). In particular, we showed that CLL cells enhance their surface expression of the immunosuppressive ligand PD-L-1 (Lopresti et al, 2024) and induce the upregulation of the inhibitory receptor PD-1 on CTLs (Boncompagni et al, 2024), leading to impaired CTL IS formation and CTL-mediated killing.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that CLL cells have the ability to rewire cellular components of the lymphoid niche, which is their primary TME, to enhance their homing to and persistence therein, where they are exposed to survival factors and protected from apoptosis-inducing drugs. These include stromal cells, which upregulate their production of homing chemokines (Patrussi et al, 2021), and CTLs themselves, which upregulate PD-1 expression (Boncompagni et al, 2024). Here we identified a new, additional immunosuppressive strategy whereby CLL cells disable CTLs by downregulating the expression of key components of their cytotoxic machinery.…”

Section: Discussionmentioning

confidence: 99%

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Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity

Cassioli,

Capitani,

Staton

et al. 2024

Preprint

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Supramolecular Attack Particles (SMAPs) are particulate entities, characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a glycoproteic shell, released by CTLs and NK cells. Prior proteomic analysis identified thrombospondin-1 (TSP-1) and thrombospondin-4 (TSP-4) as putative components of SMAPs. While TSP-1 has been validated as a component of the SMAP shell and shown to contribute significantly to CTL-mediated killing, the expression and function of TSP-4 in CTLs, and its interplay with TSP-1 in SMAP biogenesis and function, has not been investigated as yet. Here we demonstrate that TSP-4 and TSP-1 have a complementary expression profile during in vitro human CD8+ T cell differentiation to CTLs and sequentially localize to lytic granules (LG), with TSP-4 being required for TSP-1 association with LGs. Correlative light microscopy identified the TSP-enriched LGs as the SMAP-containing multicore granules. We show by STED microscopy a heterogeneity among TSP-enriched LGs, the most abundant population being positive for both TSP-4 and TSP-1. We also show that TSP-1 and TSP-4 are co-released in association with SMAPs at immune synapses formed on planar supported lipid bilayers, as assessed by dSTORM imaging. Finally, we provide evidence that TSP-4 is required for CTL- and SMAP-mediated cell killing. Of note, we found that chronic lymphocytic leukemia (CLL) cell supernatants, which suppress CTL mediated killing, also suppress expression of TSP-4 as well as of cytolytic effectors and impair SMAP biogenesis. These results identify TSP-4 as a key player in SMAP structure and activity and suggest that SMAPs may be a new target for immune suppression by CLL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity

Cassioli,

Capitani,

Staton

et al. 2024

Preprint

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“…7F, Supplementary Table 4), suggesting that the response of CLL patients to BTK inhibitors results, at least in part, from the normalization of IL-9 release by leukemic cells. Abnormal IL-9 secretion by leukemic cells of CLL patients [17,[31][32][33] and E-TCL1 mice [17] correlates with aggressive disease hallmarks, such as unmutated IGHV, low p66Shc levels [15,17], and lower overall survival [17]. The pro-tumoral activity of IL-9 involves its ability to promote homing chemokine secretion by stromal cells of lymphoid organs [15,17], thereby attracting CLL cells to the pro-survival lymphoid niche.…”

Section: Ex Vivo and In Vivo Inhibition Of Btk Enhances Il-9 Expressi...mentioning

confidence: 99%

“…Abnormal IL-9 secretion by leukemic cells of CLL patients [17,[31][32][33] and E-TCL1 mice [17] correlates with aggressive disease hallmarks, such as unmutated IGHV, low p66Shc levels [15,17], and lower overall survival [17]. The pro-tumoral activity of IL-9 involves its ability to promote homing chemokine secretion by stromal cells of lymphoid organs [15,17], thereby attracting CLL cells to the pro-survival lymphoid niche. Here we found that IL-9 secreted by CLL cells also participates in their escape from CTL-mediated killing by hampering IS formation in CTLs.…”

Section: Ex Vivo and In Vivo Inhibition Of Btk Enhances Il-9 Expressi...mentioning

confidence: 99%

“…Within the TME, CLL cells secrete cytokines and chemokines which sustain and fuel protumorigenic loops [13][14][15], as exemplified by Interleukin (IL)-10, that suppresses the ability 5 of monocytes/macrophages to produce TNF- [16], and IL-9, released by CLL cells from patients with aggressive disease, that stimulates stromal cells to secrete homing chemokines, which in turn contribute to attract CLL cells to the pro-survival lymphoid niche [15,17]. Moreover, IL-9 blockade in the CLL mouse model E-TCL1 decreases leukemic cell invasiveness and disease burden [15,17], suggesting a role for IL-9 in CLL pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia

Boncompagni,

Tatangelo,

Lopresti

et al. 2023

Preprint

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The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eu-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adaptor whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eu-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eu-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.

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Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy

Ryba-Stanisławowska

2024

Cell Oncol.

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T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals—collectively known as immune checkpoint inhibitors (ICIs)—can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.

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Interleukin (IL)-9 Supports the Tumor-Promoting Environment of Chronic Lymphocytic Leukemia

Cited by 10 publications

References 106 publications

Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity

Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity

Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia

Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy

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