Ontology highlight
ABSTRACT:
PROVIDER: PRJNA356678 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5086420.fastq.gz | Fastqsanger.gz | |||
| SRR5086430.fastq.gz | Fastqsanger.gz | |||
| SRR5086421.fastq.gz | Fastqsanger.gz | |||
| SRR5086431.fastq.gz | Fastqsanger.gz | |||
| SRR5086422.fastq.gz | Fastqsanger.gz |
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Project description:Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.
2024-06-22 | PXD050744 | Pride
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:Colo-rectal cancer is still one of the leading causes of cancer death worldwide. In France, approximately 40 500 new cases are diagnosed each year. With more than 17 500 deaths in France in 2011, colo-rectal cancer is responsible for more than 12% of all cancer deaths, the overwhelming of deaths occurring in patients with metastatic disease.
Many studies highlight the fact that colo-rectal cancer has immunogenic properties and that host immune responses can influence survival. Recent data have provided a clearer understanding of the factors limiting the antitumor immune response in colo-rectal cancer. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) and PD ligand 1 (PD-L1) pathway.
PD-1 is expressed on activated immune cells and can link to PD-L1 express on Antigen-Presenting-Cell. Usually, this pathway is involved in promoting T-cells tolerance and preventing tissue damage in settings of chronic inflammation. In pathological context, the PD-1/PD-L1 pathway contributes to immune suppression and evasion. Many human solid tumors including colo-rectal cancer express PD-L1, and this expression is associated with a worse prognosis. The interaction of PD-1 with the ligand PD-L1 inhibits T-cell proliferation, survival, and effectors functions; induces apoptosis of tumor-specific T cells; promotes the differentiation of CD4+ T cells into immunosuppressive regulatory T cells; and increases the resistance of tumor cells to cytotoxic T lymphocytes attack. Thus, the blockage of the PD-1/PD-L1 interactions represents a logical target for cancer immunotherapy and in particular colo rectal cancer immunotherapy strategy.
Preclinical studies have shown that PD-L1 blockade improves the immune response by restoring T-cell effectors functions. Recent work in two in vivo tumor models shows a strong interest in using an anti-PD-L1 in combination with standard treatment of colo-rectal cancer (FOLFOX). In these models, the survival of mice that are treated with the combination therapy reached 40% when no mice were alive with FOLFOX treatment alone. This result may be explained, in one hand by cytotoxicity of 5FU and in the other hand by the restoration of anti-tumor immune activity of anti-PD-L1. These results suggest that the combination of chemotherapy with immunotherapy would act synergistically in patients with colo-rectal cancer.
Research Hypothesis: Combination of chemotherapy (FOLFOX) with immunotherapy association (anti-PD-L1 + anti-CTLA-4) would act synergistically in patients with colo-rectal cancer.
| 2248189 | ecrin-mdr-crc
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:Tumour-associated macrophages (TAMs) are a universal feature of cancers but variably influence outcome and treatment responses. Here, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived (md)TAMs that were enriched at the tumour core, from resident-like (r)TAMs that localised with fibroblasts at the tumour–normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumour entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II– mdTAMs, demonstrating increased capacity for endocytosis and FcγR-mediated phagocytosis, as well as pro-inflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumour dwell-time. Treatment with anti-PD-L1 skewed mdTAM differentiation towards the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumour environment. Anti-PD-L1 enhanced mdTAM–CD4+ T-cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial and functional properties of TAMs, and provide evidence of subset-specific effects of PD-L1 blockade.
2025-06-07 | GSE298881 | 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
Project description:Modelling of anti-tumour immune response: Immunocorrective effect
of weak centimetre electromagnetic waves
O.G. Isaeva* and V.A. Osipov
Bogoliubov Laboratory of Theoretical Physics, Joint Institute for Nuclear Research, Dubna,
Moscow Region, Russia
We formulate the dynamical model for the anti-tumour immune response based on
intercellular cytokine-mediated interactions with the interleukin-2 (IL-2) taken into
account. The analysis shows that the expression level of tumour antigens on antigen
presenting cells has a distinct influence on the tumour dynamics. At low antigen
presentation, a progressive tumour growth takes place to the highest possible value.
At high antigen presentation, there is a decrease in tumour size to some value when the
dynamical equilibrium between the tumour and the immune system is reached. In the
case of the medium antigen presentation, both these regimes can be realized depending
on the initial tumour size and the condition of the immune system. A pronounced
immunomodulating effect (the suppression of tumour growth and the normalization of
IL-2 concentration) is established by considering the influence of low-intensity
electromagnetic microwaves as a parametric perturbation of the dynamical system. This
finding is in qualitative agreement with the recent experimental results on
immunocorrective effects of centimetre electromagnetic waves in tumour-bearing mice.
Keywords: carcinogenesis; interleukin-2; modelling; anti-tumour immunity;
electromagnetic waves
2024-09-02 | BIOMD0000000910 | BioModels
Project description:The histocompatibility barrier prevents transmission of both normal and tumour cells between individuals 1, however clonally transmissible cancers in dogs, Tasmania devils and soft-shell clams can naturally transmit as allografts 2. To understand how tumours can escape the histocompatibility barrier, we have serially passaged a mouse melanoma first into syngeneic mice and then into progressively more mismatched mouse strains until a fully allo-transplantable tumour emerged. Here we show that tumour passaging selected for cells with an anti-viral inflammatory signature, characterised by expression of MHC-I, PD-L1, Qa-1 non-classical MHC molecules and the upregulation of intergenic endogenous retroviral elements (ERVs). Knock-out of RNA sensor RIG-I 3 in the transplantable tumour cells resulted in reduced expression of MHC-I, PD-L1 and Qa-1. Antibody-mediated blockade of both PD-L1 and Qa-1 induced tumour regression after transplantation. A similar inflammatory signature was found in human melanomas that respond to anti-PD1 antibody treatment. Thus, an inflammatory anti-viral signature likely induced by RIG-I sensing of ERVs facilitates escape of the mouse melanoma from allogeneic rejection. The results underscore the immunological plasticity of melanoma and reveal an unanticipated role for inflammation in allograft immune evasion.
2025-07-29 | GSE288897 | GEO
Project description:The histocompatibility barrier prevents transmission of both normal and tumour cells between individuals 1, however clonally transmissible cancers in dogs, Tasmania devils and soft-shell clams can naturally transmit as allografts 2. To understand how tumours can escape the histocompatibility barrier, we have serially passaged a mouse melanoma first into syngeneic mice and then into progressively more mismatched mouse strains until a fully allo-transplantable tumour emerged. Here we show that tumour passaging selected for cells with an anti-viral inflammatory signature, characterised by expression of MHC-I, PD-L1, Qa-1 non-classical MHC molecules and the upregulation of intergenic endogenous retroviral elements (ERVs). Knock-out of RNA sensor RIG-I 3 in the transplantable tumour cells resulted in reduced expression of MHC-I, PD-L1 and Qa-1. Antibody-mediated blockade of both PD-L1 and Qa-1 induced tumour regression after transplantation. A similar inflammatory signature was found in human melanomas that respond to anti-PD1 antibody treatment. Thus, an inflammatory anti-viral signature likely induced by RIG-I sensing of ERVs facilitates escape of the mouse melanoma from allogeneic rejection. The results underscore the immunological plasticity of melanoma and reveal an unanticipated role for inflammation in allograft immune evasion.
2025-07-29 | GSE288825 | GEO
Project description:Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Positive cytology in ascites was a significant poor prognostic factor in ovarian cancer. Microarray profiles of cytology-positive cases showed significant correlations with Gene Ontology terms related to immune system process. Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and positive cytology. PD-L1 expression on mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and upon co-culturing with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in human ovarian cancer tissue from ascites-cytology-positive or -negative patients.
2012-07-09 | E-GEOD-39204 | biostudies-arrayexpress