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Project description:Pomalidomide inhibits PD-L1 induction to promote anti-tumor immunity
| PRJNA494725 | ENA
Project description:High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death-ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti-PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.
| S-EPMC3904601 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE31421: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] GSE31451: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH] Refer to individual Series
2011-09-30 | E-GEOD-31452 | biostudies-arrayexpress
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
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.
2022-08-18 | GSE211257 | GEO
Project description:To identify which E3 ligases ubiquitinate PD-L1, we overexpressed PD-L1-Flag in HEK293 cells and used anti-Flag magnetic beads to pull down PD-L1 from cell lysates. The interacting proteins were then analyzed by mass spectrometry, revealing that three E3 ligases interact with PD-L1.
2025-05-07 | PXD057691 | Pride
Project description:Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance.
2021-08-19 | GSE177900 | GEO
Project description:The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer-cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 maintenance and upregulation of PD-L1 upon CD58 loss. Competition by CD58 and PD-L1 for CMTM6 (via both extracellular loop domains) determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.
2023-07-06 | PXD039710 | Pride
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
Project description:Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined.
2023-03-11 | PXD037102 | Pride