Dataset Information

Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses.

ABSTRACT: Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer-microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumor-derived sEVs altered CD8+ T-cell transcriptome, proteome, and metabolome, leading to decreased functions and cell exhaustion ex vivo and in vivo. Using antagomiRs and blocking antibodies, we defined specific cargo-mediated alterations on CD8+ T cells. Abrogating sEV biogenesis by Rab27a/b knockout dramatically delayed CLL pathogenesis. This phenotype was rescued by exogenous leukemic sEV or CD8+ T-cell depletion. Finally, high expression of sEV-related genes correlated with poor outcomes in CLL patients, suggesting sEV profiling as a prognostic tool. In conclusion, sEVs shape the immune microenvironment during CLL progression.

Significance

sEVs produced in the leukemia microenvironment impair CD8+ T-cell mediated antitumor immune response and are indispensable for leukemia progression in vivo in murine preclinical models. In addition, high expression of sEV-related genes correlated with poor survival and unfavorable clinical parameters in CLL patients. See related commentary by Zhong and Guo, p. 5. This article is highlighted in the In This Issue feature, p. 1.

SUBMITTER: Gargiulo E

PROVIDER: S-EPMC9816815 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses.

Gargiulo Ernesto E Viry Elodie E Morande Pablo Elías PE Largeot Anne A Gonder Susanne S Xian Feng F Ioannou Nikolaos N Benzarti Mohaned M Kleine Borgmann Felix Bruno FB Mittelbronn Michel M Dittmar Gunnar G Nazarov Petr V PV Meiser Johannes J Stamatopoulos Basile B Ramsay Alan G AG Moussay Etienne E Paggetti Jérôme J

Blood cancer discovery 20230101 1

Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer-microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumo ...[more]

PMID: 36108149

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Project description:BackgroundThe CDK4/6 inhibitor abemaciclib is an FDA-approved agent and induces T-cell-mediated immunity. Previously, we confirmed the therapeutic potential of abemaciclib on mismatch repair-deficient (dMMR) tumors in mice. Here, we applied a prophylactic administration/dosage setting using two preclinical mouse models of dMMR-driven cancer.MethodsMlh1-/- and Msh2loxP/loxP mice received repeated prophylactic applications of abemaciclib mesylate (75 mg/kg bw, per oral) as monotherapy or were left untreated. Blood phenotyping and multiplex cytokine measurements were performed regularly. The tumor microenvironment was evaluated by immunofluorescence and Nanostring-based gene expression profiling. Numbers, size and immune composition and activity of extracellular vesicles (EVs) were studied at the endpoint.FindingsProphylactic abemaciclib-administration delayed tumor development and significantly prolonged overall survival in both mouse strains (Mlh1-/-: 50.0 wks vs. control: 33.9 wks; Msh2loxP/loxP;TgTg(Vil1-cre: 58.4 wks vs. control 44.4 wks). In Mlh1-/- mice, pro-inflammatory cytokines (IL-2, IL-6) significantly increased, whereas IL-10 and IL-17A decreased. Circulating and splenic exhausted and regulatory T cell numbers were significantly lower in the abemaciclib groups. Deeper analysis of late-onset tumors revealed activation of the Hedgehog and Notch signaling in Mlh1-/- mice, and activation of the MAPK pathway in Msh2loxP/loxP;TgTg(Vil1-cre mice. Still, arising tumors had fewer infiltrating myeloid-derived suppressor cells (vs. control). Notably, prophylactic abemaciclib-administration prevented secretion of procoagulant EVs but triggered release of immunomodulatory EVs in Mlh1-/- mice.InterpretationProphylactic abemaciclib prolongs survival via global immunomodulation. Prophylactic use of abemaciclib should be considered further for individuals with inherited dMMR.FundingThis work was supported by grants from the German research foundation [DFG grant number: MA5799/2-2] and the Brigitte und Dr. Konstanze Wegener-Stiftung to CM.

Dataset Information

Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses.

Significance

Publications

Extracellular Vesicle Secretion by Leukemia Cells In Vivo Promotes CLL Progression by Hampering Antitumor T-cell Responses.

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