Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8+ T and NK cells

Sarsembayeva, Arailym; Kienzl, Melanie; Gruden, Eva; Ristic, Dusica; Maitz, Kathrin; Valadez-Cosmes, Paulina; Santiso, Ana; Hasenoehrl, Carina; Brčić, Luka; Lindenmann, Joerg; Kargl, Julia; Schicho, Rudolf

doi:10.3389/fimmu.2022.997115

Cited by 16 publications

(15 citation statements)

References 76 publications

(119 reference statements)

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“…Flow cytometry and fluorescent microscopy analysis confirmed that NK cells express high CB2 protein levels, albeit showing a considerable variability among donors [22]. A similarly high CB2/CB1 ratio was also observed in NK cells, infiltrating in human and murine lung cancer [25].…”

Section: Canonical Cb1 and Cb2 Expression In Nk Cellsmentioning

confidence: 63%

Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?

Olivas-Aguirre,

Gutiérrez-Iñiguez,

Pottosin

et al. 2024

Receptors

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Recent research has emphasized the potential of natural and synthetic cannabinoids as anticancer agents. Yet it remains unclear whether and in which sense cannabinoids affect the anticancer activity of NK cells, an important branch of anticancer immunity. Similar uncertainty exists regarding NK cells-based immunotherapy. Here we presented an overview of multiple cannabinoid targets as canonical (mainly CB2) and non-canonical receptors, ion channels, transporters, and enzymes, expressed in NK cells, along with underlying molecular mechanisms. Through them, cannabinoids can affect viability, proliferation, migration, cytokine production, and the overall anticancer activity of NK cells. Respective holistic studies are limited, and, mostly, are phenomenological, not linking observed effects with certain molecular targets. Another problem of existing studies is the lack of standardisation, so that diverse cannabinoids at variable concentrations and ways of administration are applied, and often, instead of purified NK cells, the whole lymphocyte population is used. Therefore, there is an urgent need for more focused, systemic, and in-depth studies of the impact of the cannabinoid toolkit on NK cell function, to critically address the compatibility and potential synergies between NK activity and cannabinoid utilization in the realm of anticancer interventions.

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Section: Canonical Cb1 and Cb2 Expression In Nk Cellsmentioning

confidence: 63%

Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?

Olivas-Aguirre,

Gutiérrez-Iñiguez,

Pottosin

et al. 2024

Receptors

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“…Heterotopic tumor models are frequently used to investigate ways of influencing the TME. Recent publications showcase the use of the KP cell line as means to examine the possibility of switching a "cold" tumor into a "hot" tumor [49,50]. In this context, our group showed an improved response to PD-1 therapy in mice bearing KP cell tumors in which the cannabinoid-receptor 2 was absent in the TME [49].…”

Section: Discussionmentioning

confidence: 76%

“…Recent publications showcase the use of the KP cell line as means to examine the possibility of switching a "cold" tumor into a "hot" tumor [49,50]. In this context, our group showed an improved response to PD-1 therapy in mice bearing KP cell tumors in which the cannabinoid-receptor 2 was absent in the TME [49]. In MC38 tumors, the depletion of CD4 + T cells, CD25 + (T regs), or macrophages reduced tumor growth and supported PD-1 therapy [35].…”

Section: Discussionmentioning

confidence: 99%

Comparative Study of the Immune Microenvironment in Heterotopic Tumor Models

Kienzl,

Maitz,

Sarsembayeva

et al. 2024

Cancers

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The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A “hot” tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. “Cold” tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has focused on converting “cold” tumors into “hot” tumors to enhance the success of immunotherapy. A prerequisite for the studies of the TME is an accurate knowledge of the cell populations of the TME. This study aimed to describe the immune TME of lung and colorectal cancer and melanoma, focusing on lymphoid and myeloid cell populations. We induced heterotopic immunocompetent tumors in C57BL/6 mice, using KP and LLC (Lewis lung carcinoma) cells for lung cancer, MC38 cells for colorectal cancer, and B16-F10 cells for melanoma. Immune cell infiltration was analyzed using multicolor flow cytometry in single-cell suspensions after tumor excision. KP cell tumors showed an abundance of neutrophils and eosinophils; however, they contained much less adaptive immune cells, while LLC cell tumors predominated in monocytes, neutrophils, and monocyte-derived dendritic cells. Monocytes and neutrophils, along with a significant T cell infiltration, were prevalent in MC38 tumors. Lastly, B16-F10 tumors were enriched in macrophages, while showing only moderate T cell presence. In conclusion, our data provide a detailed overview of the immune TME of various heterotopic tumors, highlighting the variabilities in the immune cell profiles of different tumor entities. Our data may be a helpful basis when investigating new immunotherapies, and thus, this report serves as a helpful tool for preclinical immunotherapy research design.

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“…Single cell suspensions of human esophageal mucosal biopsies were prepared according to digestion procedure published for dissected tumor tissue with minor modifications ( 27 , 28 ). Using surgical scissors, 2 fresh biopsies (proximal and distal) per patient were cut into small pieces, and afterwards digested with DNase I (160 U/mL; Worthington) and collagenase (4.5 U/mL; Worthington) for 20 min at 37°C, while rotating at 750 rpm.…”

Section: Methodsmentioning

confidence: 99%

Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis

Gruden,

Kienzl,

Ristic

et al. 2024

Front. Immunol.

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IntroductionEosinophilic esophagitis (EoE) is a chronic, inflammatory, antigen-driven disease of the esophagus. Tissue EoE pathology has previously been extensively characterized by novel transcriptomics and proteomic platforms, however the majority of surface marker determination and screening has been performed in blood due to mucosal tissue size limitations. While eosinophils, CD4+ T cells, mast cells and natural killer (NK) T cells were previously investigated in the context of EoE, an accurate picture of the composition of peripheral blood mononuclear cells (PBMC) and their activation is missing.MethodsIn this study, we aimed to comprehensively analyze the composition of peripheral blood mononuclear cells and their activation using surface marker measurements with multicolor flow cytometry simultaneously in both blood and mucosal tissue of patients with active EoE, inactive EoE, patients with gastroesophageal reflux disease (GERD) and controls. Moreover, we set out to validate our data in co-cultures of PBMC with human primary esophageal epithelial cells and in a novel inducible mouse model of eosinophilic esophagitis, characterized by extensive IL-33 secretion in the esophagus.ResultsOur results indicate that specific PBMC populations are enriched, and that they alter their surface expression of activation markers in mucosal tissue of active EoE. In particular, we observed upregulation of the immunomodulatory molecule CD38 on CD4+ T cells and on myeloid cells in biopsies of active EoE. Moreover, we observed significant upregulation of PD-1 on CD4+ and myeloid cells, which was even more prominent after corticosteroid treatment. With co-culture experiments we could demonstrate that direct cell contact is needed for PD-1 upregulation on CD4+ T cells. Finally, we validated our findings of PD-1 and CD38 upregulation in an inducible mouse model of EoE.DiscussionHerein we show significant alterations in the PBMC activation profile of patients with active EoE in comparison to inactive EoE, GERD and controls, which could have potential implications for treatment. To our knowledge, this study is the first of its kind expanding the multi-color flow cytometry approach in different patient groups using in vitro and in vivo translational models.

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Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8+ T and NK cells

Cited by 16 publications

References 76 publications

Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?

Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?

Comparative Study of the Immune Microenvironment in Heterotopic Tumor Models

Mononuclear cell composition and activation in blood and mucosal tissue of eosinophilic esophagitis

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