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CD11b⁺DIP2A⁺LAG3⁺ cells facilitate immune dysfunction in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, and tumor metastasis is the leading cause of death. Targeting immune inhibitory checkpoint inhibitory pathways has attracted great attention, since the therapeutic efficacy induced by the specific blocking antibodies has been demonstrated even in metastatic CRC patients. However, the clinical outcome is low in many cases, and thus more effective treatments are needed in the clinical settings. A SPARC family member follistatin-like 1 (FSTL1) is known as a key driver of tumor metastasis in various types of cancer. However, the immunological roles of the FSTL1 in the CRC pathogenesis remain to be elucidated. In this study, we investigated the molecular mechanisms underlying the refractory FSTL1⁺ CRC using murine and human FSTL1-transduced CRC cells. Also, based on the results, we evaluated anti-tumor efficacy induced by agents targeting the identified molecules using murine CRC metastasis models, and validated the clinical relevancy of the basic findings using tumor tissues and peripheral blood obtained from CRC patients. FSTL1 transduction conferred EMT-like properties, such as low proliferative (dormant) and high invasive abilities, on tumor cells. When the transfectants were subcutaneously implanted in mice, CD11b⁺DIP2A⁺LAG3⁺ cells were abundantly expanded locally and systemically in the mice. Simultaneously, apoptotic T cells increased and were lastly excluded from the tumor tissues, allowing tumor aggravation leading to resistance to anti-PD1/PDL1 treatment. Blocking FSTL1 and LAG3, however, significantly suppressed the apoptosis induction, and successfully induced anti-tumor immune responses in the CRC metastasis models. Both treatments synergized in providing better prognosis of the mice. FSTL1 was significantly upregulated in tumor tissues and peripheral blood of CRC patients, and the CD11b⁺DIP2A⁺LAG3⁺ cells were significantly expanded in the PBMCs as compared to those of healthy donors. The expansion level was significantly correlated with decrease of potent Ki67⁺GZMB⁺ CTLs. These results suggest that the FSTL1-induced CD11b⁺DIP2A⁺LAG3⁺ cells are a key driver of immune dysfunction in CRC. Targeting the FSTL1-LAG3 axis may be a promising strategy for treating metastatic CRC, and anti-FSTL1/LAG3 combination regimen may be practically useful in the clinical settings.

SUBMITTER: Kudo-Saito C

PROVIDER: S-EPMC8640801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveImmature CD11b + Gr1+ myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study's objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b+Gr1+ myeloid cells.MethodsAll studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti-PD1 mAb. The treatment effect was assessed by a survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess the protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies.ResultsThe depletion of Gr1+ immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. In addition to the adoptive transfer studies, these findings validate the role of immunosuppressive CD11b+Gr1+ myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironments produced recruitment and regulatory factors for immunosuppressive CD11b+Gr1+ myeloid cells. CD11b+Gr1+ myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted primarily by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers' expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found to be the most significantly elevated gene in tumor-primed myeloid cells. The inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression and function in myeloid cells.ConclusionOur study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b + Gr1+ myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in immunosuppressive myeloid cells decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer.

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CD11b⁺DIP2A⁺LAG3⁺ cells facilitate immune dysfunction in colorectal cancer.

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CD11b+DIP2A+LAG3+ cells facilitate immune dysfunction in colorectal cancer.

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OmicsDI is part of the ELIXIR infrastructure

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CD11b⁺DIP2A⁺LAG3⁺ cells facilitate immune dysfunction in colorectal cancer.