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Project description:The cellular and molecular mechanisms underlying tumor cell PD-L1 (tPD-L1) function in tumor immune evasion are incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activity in co-cultures of tumor cells and tumor-specific CTLs and exhibits no effect on primary tumor growth. However, deleting tPD-L1 decreases lung metastasis in a CTL-dependent manner in tumor-bearing mice. Depletion of myeloid cells or knocking out PD-1 in myeloid cells (mPD-1) impairs tPD-L1 promotion of tumor lung metastasis in mice. Single-cell RNA sequencing (scRNA-seq) reveals that tPD-L1 engages mPD-1 to activate SHP2 to antagonize the type I interferon (IFN-I) and STAT1 pathway to repress Cxcl9 and impair CTL recruitment to lung metastases. Human cancer patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our findings determine that tPD-L1 engages mPD-1 to activate SHP2 to suppress the IFN-I-STAT1-CXCL9 pathway to impair CTL tumor recruitment in lung metastasis.
| S-EPMC10150625 | biostudies-literature
Project description:A hallmark of PD-1/L1 blockade is long-term, sustained remission of metastatic disease. How the immune system coordinates the destruction of macro- and micro-metastases following checkpoint blockade, however, remains unclear. Here, we show that tumor-expressed PD-L1 (tPD-L1) enhanced metastasis in a mechanism distinct from and independent of its role in primary tumor growth. This difference in metastatic growth was mediated by cytotoxic T lymphocytes (CTLs), however, tPD-L1 did not promote effector CTL exhaustion or suppress lytic activity in vivo. Instead, single cell RNA sequencing revealed that tPD-L1 engaged macrophage-expressed PD-1 to antagonize type I interferon production and signaling, creating an immunologically ‘cold’ microenvironment. Loss of tPD-L1 eliminated metastases by driving interferon-mediated sensitization of tumor cells to CTL lysis and CTL recruitment.
2023-02-06 | GSE150739 | GEO
Project description:A hallmark of PD-1/L1 blockade is long-term, sustained remission of metastatic disease. How the immune system coordinates the destruction of macro- and micro-metastases following checkpoint blockade, however, remains unclear. Here, we show that tumor-expressed PD-L1 (tPD-L1) enhanced metastasis in a mechanism distinct from and independent of its role in primary tumor growth. This difference in metastatic growth was mediated by cytotoxic T lymphocytes (CTLs), however, tPD-L1 did not promote effector CTL exhaustion or suppress lytic activity in vivo. Instead, single cell RNA sequencing revealed that tPD-L1 engaged macrophage-expressed PD-1 to antagonize type I interferon production and signaling, creating an immunologically ‘cold’ microenvironment. Loss of tPD-L1 eliminated metastases by driving interferon-mediated sensitization of tumor cells to CTL lysis and CTL recruitment.
2023-02-06 | GSE150742 | GEO
Project description:Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment
| PRJNA633487 | ENA
Project description:Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (bulk)
| PRJNA633486 | ENA
Project description:Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (single cells)
| PRJNA633497 | ENA
Project description:During systemic inflammation different neutrophil subsets are mobilized to the peripheral blood. These neutrophil subsets can be distinguished from normal circulating neutrophils (CD16(bright)/CD62L(bright)), based on either an immature CD16(dim)/CD62L(bright) or a CD16(bright)/CD62L(dim) phenotype. Interestingly, the latter neutrophil subset is known to suppress lymphocyte proliferation ex vivo, but how neutrophils become suppressive is unknown. We performed transcriptome analysis on the different neutrophil subsets to identify changes in mRNA expression that are relevant for their functions. Neutrophil subsets were isolated by fluorescence-activated cell sorting from blood of healthy volunteers that were administered a single dose of lipopolysaccharide (2 ng/kg i.v.) and the transcriptome was determined by microarray analysis. Interestingly, the CD16(bright)/CD62L(dim) suppressive neutrophils showed an interferon-induced transcriptome profile. More importantly, IFN-?, but not IFN-? or IFN-? stimulated neutrophils, acquired the capacity to suppress lymphocyte proliferation through the expression of programmed death ligand 1 (PD-L1). These data demonstrate that IFN-?-induced expression of PD-L1 on neutrophils enables suppression of lymphocyte proliferation. Specific stimulation of neutrophils present at the inflammatory sites might therefore have a pivotal role in regulating lymphocyte-mediated inflammation and autoimmune disease.
| S-EPMC3756078 | biostudies-literature
Project description:Smac-mimetics are emerging as promising anti-cancer agents and are being evaluated in clinical trials for a variety of malignancies. Smac-mimetics can induce TNF production from a subset of tumor cells and simultaneously sensitize them to TNF-induced apoptosis. However, TNF derived from other cellular sources, such as cytotoxic lymphocytes (CLs) within the tumor, may also contribute to the anti-tumor activity of SMs. Here, we show that CD8+ T cells and NK cells potently kill tumor cells in the presence of the SM, birinapant. Enhanced CL killing occurred through TNF secretion upon tumor antigen recognition or NK-activating receptor ligation. Importantly, the perforin/granzyme route to CL-mediated tumor cell killing was dispensable for the efficacy of birinapant, emphasizing the importance of the TNF-mediated apoptosis pathway. Time-lapse microscopy revealed that birinapant sensitized tumor cells to apoptosis as bystanders and to membrane-bound TNF delivered to tumor cells within the immunological synapse. Furthermore, PD-L1 expression on tumor cells suppressed antigen-driven TNF production by CD8+ T cells, which could be antagonized through PD-1 blockade. Importantly, the elevated levels of TNF produced upon PD-1 blockade further enhanced tumor cell killing when combined with birinapant. The combined anti-tumor activity of IAP antagonism and PD-1 blockade occurred independently of perforin-mediated tumor cell death. Taken together, we identify CL-derived TNF as a potent effector of birinapant mediated anti-tumor immunity and opportunity for combination therapy through co-inhibition of immune checkpoints.
| S-EPMC5596429 | biostudies-literature
Project description:Background and objectives: Cytotoxic T-lymphocyte (CTL)-mediated inflammatory response to tumors plays a crucial role in preventing the progression of some cancers. Programmed cell death ligand 1 (PD-L1), a cell-surface glycoprotein, has been reported to repress T-cell-mediated immune responses against tumors. However, the clinical significance of PD-L1 in colorectal cancer (CRC) remains unclear. Our aim was to elucidate the prognostic significance of PD-L1 expression and CD8+ CTL density in CRC. Materials and methods: CD8 and PD-L1 immunostaining was conducted on 157 pathologic specimens from patients with CRC. The CD8+ CTL density and PD-L1 expression within the tumor microenvironment were assessed by immunohistochemistry. Results: Tumor invasion (pT) was significantly correlated with intratumoral (p = 0.011) and peritumoral (p = 0.016) CD8+ CTLs density in the tumor microenvironment. In addition, there was a significant difference in the intensity of CD8+ CTLs between patients with and without distant metastases (intratumoral p = 0.007; peritumoral p = 0.037, T-test). Lymph node metastasis (pN) and TNM stage were significantly correlated with PD-L1 expression in CRC cells (p = 0.015, p = 0.029, respectively). Multivariate analysis revealed a statistically significant relationship between the intratumoral CD8+ CTL density and disease-free survival (DFS) (hazard ratio [HR] 2.06; 95% confidence interval [CI]: 1.01-4.23; p = 0.043). The DFS was considerably shorter in patients with a high expression of PD-L1 in cancer cells than those with a low expression (univariate HR 2.55; 95% CI 1.50-4.34; p = 0.001; multivariate HR 0.48; 95% CI 0.28-0.82; p = 0.007). Conversely, patients with high PD-L1 expression in tumor-infiltrating lymphocytes had a longer DFS in both univariate analysis (HR 0.25; 95% CI: 0.14-0.44; p < 0.001) and multivariate analysis (HR 3.42; 95% CI: 1.95-6.01; p < 0.001). Conclusion: The CD8+ CTL density and PD-L1 expression are prognostic biomarkers for the survival of patients with CRC.
| S-EPMC6915478 | biostudies-literature
Project description:Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-? treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-? treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-? in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-? treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
| S-EPMC7400993 | biostudies-literature