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Fusobacterium nucleatum Induces PD-L1 Expression by Tumor-Associated Macrophages and Inhibits Anti-Tumor Immunity in Colorectal Cancer.

ABSTRACT: Fusobacterium nucleatum (Fn) infection has been linked to the initiation and development of colorectal cancer (CRC). However, the underlying mechanisms remains unexplored. Tissues from Fn-infected mice were first collected for single-cell RNA sequencing. we investigated the correlation between Fn infection and accumulations of tumor associated macrophages (TAMs) in tissues from human CRC or AOM/DSS treated mice. The impact of Fn on biological function of TAMs were interrogated. We deciphered the mechanisms for interaction between Fn and TAMs in CRC. We explored the impact of Fn infection on immune-checkpoint blockade (ICB) treatment in a multicohort study.The analysis of single-cell RNA sequencing revealed an enrichment of TAMs in Fn positive tissues. A significant correlation between Fn DNA level and TAMs was observed. Functionally, Fn could recruit TAMs in CRC tissues and promote their biological functions by enhancing PD-L1 expression and thus suppressing CD8+ T cells. Mechanistically, Fn infection led to increased secreted IL-6 via TLR4/MyD88/NF-κB pathways, and the activated IL-6/STAT3 pathway enhanced PD-L1 expression in TAMs. By using several mice models, we found IL-6 inhibition, loss of MyD88 or anti-PD-L1 treatment could significantly inhibit tumorigenesis. Clinically, Fn positive patients tended to be more sensitive to ICB treatment, with a better prognosis than Fn-negative patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE211257 | GEO | 2022/08/18

REPOSITORIES: GEO

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Fusobacterium nucleatum Induces PD-L1 Expression by Tumor-Associated Macrophages and Inhibits Anti-Tumor Immunity in Colorectal Cancer.

Project description:Fusobacterium nucleatum (Fn) infection has been linked to the initiation and development of colorectal cancer (CRC). However, the underlying mechanisms remains unexplored. Tissues from Fn-infected mice were first collected for single-cell RNA sequencing. we investigated the correlation between Fn infection and accumulations of tumor associated macrophages (TAMs) in tissues from human CRC or AOM/DSS treated mice. The impact of Fn on biological function of TAMs were interrogated. We deciphered the mechanisms for interaction between Fn and TAMs in CRC. We explored the impact of Fn infection on immune-checkpoint blockade (ICB) treatment in a multicohort study.The analysis of single-cell RNA sequencing revealed an enrichment of TAMs in Fn positive tissues. A significant correlation between Fn DNA level and TAMs was observed. Functionally, Fn could recruit TAMs in CRC tissues and promote their biological functions by enhancing PD-L1 expression and thus suppressing CD8+ T cells. Mechanistically, Fn infection led to increased secreted IL-6 via TLR4/MyD88/NF-κB pathways, and the activated IL-6/STAT3 pathway enhanced PD-L1 expression in TAMs. By using several mice models, we found IL-6 inhibition, loss of MyD88 or anti-PD-L1 treatment could significantly inhibit tumorigenesis. Clinically, Fn positive patients tended to be more sensitive to ICB treatment, with a better prognosis than Fn-negative patients.

2024-04-19 | GSE172334 | GEO

Phagocytes as Trojan horse for Fusobacterium nucleatum routing to the tumor tissues and enhance tumor metastasis

Project description:The facultative intracellular bacterium Fusobacterium nucleatum (Fn), mediates tumorigenesis and progression in CRC. However, the origin of intracellular Fn and the role of Fn-infected phagocytes in tumor microenvironment remains unclear. Here, we observed Fn-infected neutrophils/macrophages (PMNs/MΦ) is accumulated in CRC tumor tissues. Fn can survive inside of PMNs by reducing intracellular ROS levels. The lysozyme inhibitor Fn-MliC induced the expression of the CX3CR1 which suppressed apoptosis of phagocytes. Fn-infected phagocytes can transfer Fn to tumor cells, and Fn-infected CRC cells recruited PMNs and MΦ/monocytes through the CXCL2/8-CXCR2 and CCL5/CCR5 axis. Intracellular Fn upregulated PD-L1 expression through activating NF-κB/STAT3 pathway in PMNs. PD-L1+ PMNs infiltration promotes CRC metastasis and weaken the efficacy of immunotherapy, and eradication intracellular Fn infection retarded the Fn promoted tumor progressing in mice. These results suggest that Fn volved efficient strategies to exploit phagocytes to home to tumor tissues, inhibited immune responses and facilitate tumor metastasis.

2024-01-01 | GSE243383 | GEO

MyD88/IL-1R axis sustains immunosuppressive function of TAMs by regulating PD-1 expression in melanoma

Project description:Macrophages are critical mediators of tissue homeostasis, cell proliferation, angiogenesis and tumor metastasis. The presence of TAMs is generally associated with tumor-promoting immunosuppressive function in solid tumors. These macrophages are widely acknowledged as one of the central suppressive populations within tumors, blocking effective T-cell responses. In the present study, we examined the transcriptional landscape of adaptor molecules downstream of TLRs in human cancers and found that higher expression of MYD88 is very well correlated with the tumor progression. In addition, we also found that mouse MyD88 but not TRIF, is essential for tumor progression and angiogenesis in melanoma. Interestingly, MyD88 is critical to maintain the immunosuppressive phenotype of TAMs in the tumors. Moreover, we found that interleukin-1 receptor (IL-1R)-Myd88 axis regulates programmed cell death (PD)-1 expression on TAMs by promoting the recruitment of phospho-NF-κB p65 to the CR-C region of the Pdcd1 promoter. Using myeloid-cell specific MyD88 mutant mice, we also showed that MyD88 expression in myeloid cells alone is sufficient to drive the melanoma progression. Thus, IL-1R/MyD88 axis maintains the immunosuppressive function of tumor-tissue macrophages to promote tumor growth by regulating PD-1/PD-L1 expression

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DRG2 is required for cell surface localization of PD-L1 in melanoma cells and optimum response to anti-PD-1 immune checkpoint blockade [scRNA-seq]

Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.

2023-11-06 | GSE231973 | GEO

DRG2 is required for cell surface localization of PD-L1 in melanoma cells and optimum response to anti-PD-1 immune checkpoint blockade [bulk RNA-seq]

2023-11-06 | GSE231972 | GEO

IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction

Project description:Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell-type specific deletion of IL-10- and IL-10Ra were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of IL-10 on PD-L1. Results: We found that Il10-deficient mice and mice treated with IL-10Ra antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e., monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer (CRC)-derived liver metastasis. These findings provide the basis for future monitoring and targeting of IL-10 in CRC-derived liver metastasis.

2024-02-09 | GSE247304 | GEO

Nuclear compartmentalization of PD-L1 suppresses tumorigenesis and overcomes immunocheckpoint therapy resistance via histone macroH2A1 phosphorylation

Project description:Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more significantly in immunocompetent mice. p-AMPKα facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK-STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which may result from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to IFN-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

2024-11-20 | GSE276400 | GEO

Comprehensive testing of chemotherapy and immune checkpoint blockade in preclinical cancer models identifies additive combinations

Project description:Background: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA 4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. Methods: We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. Results: 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFN , TNF and IL-1β signaling. The effective anti tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNF or IL 1β cytokine signaling pathways were blocked. Conclusions: Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.

2022-05-02 | GSE188481 | GEO

Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

Project description:Immune checkpoint blockers (ICBs) targeting programmed death 1(PD-1) are considered effective first-line therapy against PD-1 ligand (PD-L1)-expressing head and neck squamous cell carcinoma (HNSCC). However, associated changes in tumor microenvironment (TME) and mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou Oral Cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC xenograft model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in TME, including vascular normalization. Furthermore, the anti-tumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and anti-vascular endothelial growth factor receptor 2 inhibitors. The ICB-induced anti-tumorigenicity and TME normalization were alleviated by blocking the Type I interferon pathway.In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the Type-I interferon pathway is indispensable in realizing ICB effects. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against HNSCC expressing PD-L1 in the KEYNOTE-048 trial. This model can assist future research on HNSCC immunotherapy.

2023-12-01 | GSE248271 | GEO

The mRNA profiles of the macrophages with or without Trastuzumab-dependent tumor phagocytosis

Project description:Therapeutic antibodies trigger antibody-dependent cellular cytotoxicity (ADCC) of cancer cells and also their antibody-dependent cellular phagocytosis (ADCP) by tumor-associated macrophages (TAMs). We report here our unexpected finding that TAMs that have undergone ADCP of tumor cells induced by therapeutic antibodies display immunosuppressive characteristics and inhibit the proliferation and tumoricidal effects of NK and tumor-specific CD8+ T cells in breast cancers and lymphomas. Mechanistically, we show that DNA released from the phagocytosed tumor cells after ADCP activates caspase 1 inflammasome, leading to IL-1β-mediated PD-L1 and IDO upregulation in these cells. Combined treatment with anti- HER2 antibody and inhibitors of PD-L1 and IDO increased the infiltration of NK and CD8+ T cells and enhanced anti- HER2 therapeutic efficacy in mouse models of HER2+ breast cancers. Furthermore, neo-adjuvant Trastuzumab therapy significantly increased PD-L1 and IDO expression in the TAMs of HER2+ breast cancer patients, which correlate with poor Trastuzumab response and reduced NK and CD8+ T cells in the tumors. Collectively, our findings unveil an unexpected role of ADCP induced by therapeutic antibodies in cancer immunosuppression, and suggest that antibody plus immune checkpoint blockade may provide synergistic therapeutic effects in cancer patients.

2018-09-04 | GSE119342 | GEO

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