T cells in pancreatic cancer stroma Goulart, Michelle R; Stasinos, Konstantinos; Fincham, Rachel Elizabeth Ann ...
World journal of gastroenterology : WJG,
2021-Dec-14, 2021-12-14, 20211214, Letnik:
27, Številka:
46
Journal Article
Odprti dostop
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a dismal 5-year survival rate. PDAC has a complex tumour microenvironment; characterised by a robust desmoplastic stroma, ...extensive infiltration of immunesuppressive cells such as immature myeloid cells, tumour-associated macrophages, neutrophils and regulatory T cells, and the presence of exhausted and senescent T cells. The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance, disease progression and spread to distant organs. PDAC tumours, considered to be non-immunogenic or cold, express low mutation burden, low infiltration of CD8
cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue, and often display an exhausted phenotype. Here, we review the role of T cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.
Abstract Background/Objectives The vascular heterogeneity of pancreatic ductal adenocarcinoma (PDAC) has never been characterised. We analysed the heterogeneous vascular density of human PDAC along ...with its prognostic correlation. Methods Tissue Microarrays of 87 patients with different pancreatico-biliary pathologies were analysed in an automated manner (Ariol™) after CD31 staining to assess vascular density in juxta-tumoral and panstromal compartments. In vitro and ex vivo assays were carried out to assess the role of PSC. Results PDAC has a distinct vascular density and distribution of vessels compared to cholangiocarcinoma. The PDAC juxta-tumoral stroma was hypovascular and the normal adjacent rim was hypervascular compared to the panstromal compartment. These features adversely affected patient prognosis, suggesting a model for spatio-temporal PDAC evolution. Mice aortic rings and 3D organotypic cultures demonstrated pro- and anti-angiogenic signalling from activated PSC and cancer cells respectively. ATRA-induced quiescence suppressed the pro-angiogenic activity of PSC. Conclusion Human PDAC has variable vascularity at microscopic level suggesting that novel stromal directed therapies would need to be determined by pathological characteristics.
The presence of tertiary lymphoid structures (TLSs) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the ...precise role in PDAC has not been elucidated. Here, we aim to investigate the structure and role of TLSs in human and murine pancreatic cancer.
Multicolor immunofluorescence and immunohistochemistry were used to fully characterize TLSs in human and murine (transgenic KPC (KrasG12D, p53R172H, Pdx-1-Cre) and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLSs and the effect of the combined chemotherapy and immunotherapy on tumor growth.
Mature, functional TLSs are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intratumoral injection of lymphoid chemokines (CXCL13/CCL21). Coadministration of systemic chemotherapy (gemcitabine) and intratumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration ,facilitating TLS induction and potentiating antitumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Antitumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation.
This study provides supportive evidence that TLS induction may potentiate the antitumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immune-oncology.
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Treatment of Organotypic Cultures (OT) and the KPC mouse (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) was performed to mimic human chemotherapy regimen cycles with All-Trans Retinoic Acid (ATRA), ...targeting PSC, and the chemotherapeutic agent gemcitabine, targeting pancreatic cancer cells (PCC).
Background and aims: The presence of tertiary lymphoid structures (TLSs) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert ...malignancy. Yet, the precise role in PDAC has not been elucidated. Here, we aim to investigate the structure and role of TLSs in human and murine pancreatic cancer. Methods: Multicolor immunofluorescence and immunohistochemistry were used to fully characterize TLSs in human and murine (transgenic KPC (KrasG12D, p53R172H, Pdx-1-Cre) and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLSs and the effect of the combined chemotherapy and immunotherapy on tumor growth. Results: Mature, functional TLSs are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intratumoral injection of lymphoid chemokines (CXCL13/CCL21). Coadministration of systemic chemotherapy (gemcitabine) and intratumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration ,facilitating TLS induction and potentiating antitumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Antitumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation. Conclusions: This study provides supportive evidence that TLS induction may potentiate the antitumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immune-oncology.
B cells in pancreatic cancer stroma Delvecchio, Francesca Romana; Goulart, Michelle R; Fincham, Rachel Elizabeth Ann ...
World journal of gastroenterology : WJG,
2022-Mar-21, 2022-3-21, 20220321, Letnik:
28, Številka:
11
Journal Article
Odprti dostop
Pancreatic cancer is a disease with high unmet clinical need. Pancreatic cancer is also characterised by an intense fibrotic stroma, which harbours many immune cells. Studies in both human and animal ...models have demonstrated that the immune system plays a crucial role in modulating tumour onset and progression. In human pancreatic ductal adenocarcinoma, high B-cell infiltration correlates with better patient survival. Hence, B cells have received recent interest in pancreatic cancer as potential therapeutic targets. However, the data on the role of B cells in murine models is unclear as it is dependent on the pancreatic cancer model used to study. Nevertheless, it appears that B cells do organise along with other immune cells such as a network of follicular dendritic cells (DCs), surrounded by T cells and DCs to form tertiary lymphoid structures (TLS). TLS are increasingly recognised as sites for antigen presentation, T-cell activation, B-cell maturation and differentiation in plasma cells. In this review we dissect the role of B cells and provide directions for future studies to harness the role of B cells in treatment of human pancreatic cancer.
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