Project description:The formation of tertiary lymphoid structures (TLSs) in tumors is significantly correlated with prolonged patient survival, better prognosis, and improved response to immunotherapy. Understanding the tumor microenvironments involved in TLS formation is crucial. This bulk RNA sequencing study utilized archived FFPE samples from PDAC patients to reveal gene expression profiles in tumors with TLS formation.
Project description:Tertiary lymphoid structures (TLS) correlate with favorable responses to immune checkpoint inhibitors (ICI) in various cancers, yet many patients with TLS-positive tumors are resistant to treatment. Multi-omic profiling of clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma tumors (STS) reveals an upregulation of gamma-aminobutyric acid (GABA)-related signatures in non-responders to ICI. In ccRCC, TLS from non-responders located near GABA-producing tumor cells, exhibit impaired B cell maturation, reduced IgG production, higher GABA receptor expression and tricarboxylic acid cycle activation. In vitro, exposure of human B cells to GABA reduces HLA-DR expression, proliferation and immunoglobulin secretion by receptor independent and dependent mechanisms. Pharmacological inhibition of GABA-synthesis increases ICI response and immune infiltration, particularly by B cells, in a TLS-positive STS mouse model. Our findings unravel GABA as an immunoregulatory metabolite and provide a rationale for its therapeutic targeting to overcome ICI resistance in patients with TLS-positive tumors.
Project description:Tertiary lymphoid structures (TLS) correlate with favorable responses to immune checkpoint inhibitors (ICI) in various cancers, yet many patients with TLS-positive tumors are resistant to treatment. Multi-omic profiling of clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma tumors (STS) reveals an upregulation of gamma-aminobutyric acid (GABA)-related signatures in non-responders to ICI. In ccRCC, TLS from non-responders located near GABA-producing tumor cells, exhibit impaired B cell maturation, reduced IgG production, higher GABA receptor expression and tricarboxylic acid cycle activation. In vitro, exposure of human B cells to GABA reduces HLA-DR expression, proliferation and immunoglobulin secretion by receptor independent and dependent mechanisms. Pharmacological inhibition of GABA-synthesis increases ICI response and immune infiltration, particularly by B cells, in a TLS-positive STS mouse model. Our findings unravel GABA as an immunoregulatory metabolite and provide a rationale for its therapeutic targeting to overcome ICI resistance in patients with TLS-positive tumors.
Project description:Pancreatic ductal adenocarcinoma (PDAC) is considered an immunologically cold cancer type. This perception is due to its rapid progression, strong presence of immunosuppressive cells and lack of response to current immunotherapies. However, we and others have shown that many patient PDAC tumors contain robust lymphocyte infiltration, aggregated in the form of tertiary lymphoid structures (TLS). The presence of TLS in PDAC is prognostic for long-term survival and in other cancer types, predictive of response to immunotherapy. Despite the clinical benefit to generating TLS in tumors, why they form in some PDAC patients but not others, remains unknown. The desmoplastic stroma in PDAC contributes to defective anti-tumor immunity largely due to myofibroblastic cancer associated fibroblasts (myCAF) induced by transforming growth factor-beta (TGF). Other groups have demonstrated that mesenchymal cell phenotypes with lymphoid tissue organizing properties regulate TLS formation in tumors. In order to restore effective anti-tumor immunity for PDAC patients, CAF phenotypes must be reprogrammed to support rather than restrict intratumoral immune activity. Using a lymphotoxin beta receptor (LTBR) agonist we observed induction of TLS-like aggregates in some murine PDAC tumor models, but not others. The CAF phenotypes of TLS-resistant models were predominantly myCAF while the TLS-permissive models were enriched for a VCAM1+ICAM1+ reticular-CAF (rCAF) subset. Induction of myCAF differentiation in vitro with TGF1 silenced LTBR/TNFR mediated upregulation of rCAF chemokine expression and attenuated B and T cell migration towards fibroblasts. Therapeutic TGFR1 inhibition ameliorated these effects thereby allowing LTBR agonism to repolarize rCAF phenotypic programming associated with improved lymphocyte recruitment and T cell-dependent tumor control. In patient PDAC tumors, rCAF resided next to TLS while myCAF were distally located. These data indicate that the myCAF-regulated PDAC stroma antagonizes acquisition of rCAF subsets critical for TLS formation but can be therapeutically remodeled to promote beneficial immune responses in immunosuppressive PDAC tumors.
Project description:Transcriptional profiling of ALDH1 high cancer stem like cells of ovarian cancer cell line, sorted out using ALDEFLUOR assay. Two-condition experiment, ALDEFLUOR positive vs. negative cells. Biological replicates: 1 ALDEFLUOR positive replicate, 1 negative replicate.
Project description:Comparison of t(11;18)-positive MALT lymphoma to t(11;18)-negative MALT lymphoma, with a special focus on the NF-KB pathway and it's targets
Project description:Transcriptional profiling of GIF-5 mouse gastric epithelial cells comparing CD133-positive and CD133-negative cells. The former formed CD133-positive and CD133-negative cells while the latter only CD133-negative cells, suggesting that CD133-positive cells are mother cells. The former produced differentiated type tumors while the latter undifferentiated types in vivo, indicating a relationship between CD133-expression and glandular structure formation.
Project description:The organoids heterogenously expressed mCherry by the lentivirus transduction were dissociated into single cells. A single mCherry- positive and -negative cell were collected and grown up to the organoids, respectivery. The difference of the gene expression profile between mCherry- positive and -negative organoids was assessd by maicroarray.