PD-L1 checkpoint blockade promotes regulatory T-cell suppressive capacity underlying immunotherapy resistance
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ABSTRACT:
PROVIDER: PRJNA735630 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptome analyses of isotype-treated and aPD-L1-treated CD4+ T-cells, PD1- Treg cells and PD1+ Treg cells from a mouse model for mesothelioma.
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Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-22 | GSE279750 | GEO
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-14 | GSE279110 | GEO
Project description:Foxp3 enhancers synergize to maximize regulatory T cell suppressive capacity
| PRJNA664381 | ENA
Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
2024-10-14 | GSE279109 | GEO
Project description:Inhibiting PD1:PDL1 signaling has transformed therapeutic immune restoration. CD4 T cells are critical to sustain immunity in chronic infections and cancer, yet little is known about how PD1/L1 modulates CD4 T helper (Th) responses or the ability to restore CD4 Th-mediated immunity by inhibiting PD1/L1 signaling. We demonstrate that PD1/L1 specifically suppresses CD4 Th1 cell amplification, prevents CD4 Th1 cytokine production, and abolishes CD4 CTL killing capacity during chronic infection. Inhibiting PDL1 during chronic infection rapidly restored these functions, while simultaneously enhancing Th1-like Treg amplification and activation, indicating a system-wide CD4-Th1 recalibration. Paradoxically, PDL1-blockade decreased TCR signaling, while re-directing intrinsically-suppressive type I interferon networks towards dominant IFNγ-mediated responses. Mechanistically, PDL1-blockade specifically targeted defined populations with pre-established, but actively-suppressed proliferative potential, with limited impact on minimally-cycling TCF1+ Tfh, despite high PD1 expression. Thus, CD4 T cells require unique differentiation and functional states to be targets of PDL1-directed suppression and therapeutic restoration.
2021-09-20 | GSE163343 | GEO
Project description:Inhibiting PD1:PDL1 signaling has transformed therapeutic immune restoration. CD4 T cells are critical to sustain immunity in chronic infections and cancer, yet little is known about how PD1/L1 modulates CD4 T helper (Th) responses or the ability to restore CD4 Th-mediated immunity by inhibiting PD1/L1 signaling. We demonstrate that PD1/L1 specifically suppresses CD4 Th1 cell amplification, prevents CD4 Th1 cytokine production, and abolishes CD4 CTL killing capacity during chronic infection. Inhibiting PDL1 during chronic infection rapidly restored these functions, while simultaneously enhancing Th1-like Treg amplification and activation, indicating a system-wide CD4-Th1 recalibration. Paradoxically, PDL1-blockade decreased TCR signaling, while re-directing intrinsically-suppressive type I interferon networks towards dominant IFNγ-mediated responses. Mechanistically, PDL1-blockade specifically targeted defined populations with pre-established, but actively-suppressed proliferative potential, with limited impact on minimally-cycling TCF1+ Tfh, despite high PD1 expression. Thus, CD4 T cells require unique differentiation and functional states to be targets of PDL1-directed suppression and therapeutic restoration.
2021-09-20 | GSE163259 | GEO
Project description:Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS
| PRJNA507717 | ENA
Project description:Introduction
Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit.
Methods
In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow HSPCs. We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality.
Results
Herein, we reveal that aPD-L1 in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice.
Discussion:
Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.
| EGAS00001007873 | EGA
Project description:Purpose: Use RNA-seq to characterize the anti-tumor immune response induced by ALPN-202 and compare to that of anti-PD-L1 treatment alone. Methods: mRNA was isolated from MC38/hPD-L1 tumors 72 hours after a single dose of ALPN-202 (n=4), anti-PD-L1 mAb (durvalumab) (n=4), or Fc control (n=4). Results: ALPN-202 treatment resulted in elevated expression of multiple T cell, NK cell, myeloid cell genes. Additionally, there was a strong increase in genes commonly associated with a proinflammatory response including cytokines, chemokines and surface markers. Conclusions: ALPN-202 treatment resulted in a strong anti-tumor immune response that was more potent than that generated by blockade of PD-L1 alone.
2022-02-10 | GSE161244 | GEO