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Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Tumour plasticity and tumour microenvironment interactions as potential immunologic targets for pancreatic cancer
Xu Zhou1, Christoph Springfeld2, Susanne Roth3
1Botton-Champalimaud Pancreatic Cancer Center, Champalimaud Foundation, Lisbon, Portugal.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer with a high mortality and limited treatment options. Systemic chemotherapy remains the only approach for improving survival in patients with unresectable locally advanced and/or metastatic disease which comprises most patients. Targeted therapies have so far been disappointing with limited applicability and improvement in overall survival. Patients with resectable PDAC have improved survival with adjuvant chemotherapy, whereas neoadjuvant chemotherapy is the best option for borderline resectable PDAC. In patients with locally advanced unresectable PDAC, resection rates may be improved with induction chemotherapy and possibly radiotherapy. Immunotherapy has proved to be relatively effective in multiple solid cancer types, and yet has shown poor or no efficacy in PDAC treatment. With the development of tumour and tumour microenvironment (TME) stratification by transcriptomic and histological profiling, we are able to have a deeper understanding of the clinical implications of TME heterogeneity and tumour plasticity. PDAC and stromal cells within the TME including cancer associated fibroblasts can be reprogrammed under certain treatment conditions to switch, at least to some extent, the whole immune-cold complex towards a more immune-hot and chemo-sensitive state. This approach may provide us with a new perspective in the design of immunotherapy and chemotherapy combination regimens.
Insights
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with few treatments. New strategies targeting the tumor microenvironment (TME) may improve immunotherapy and chemotherapy effectiveness for PDAC patients.
Area of Science:
- Oncology
- Cancer Research
- Immunotherapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant global health challenge due to its high mortality rate and limited therapeutic strategies.
- Current treatments, including systemic chemotherapy and targeted therapies, offer modest survival benefits, particularly for advanced or metastatic disease.
- Immunotherapy has shown limited efficacy in PDAC, highlighting the need for novel treatment paradigms.
Purpose of the Study:
- To explore the potential of targeting the tumor microenvironment (TME) to overcome treatment resistance in PDAC.
- To investigate the reprogramming of PDAC and associated stromal cells within the TME to enhance anti-tumor immunity and chemosensitivity.
- To provide a new perspective for designing combination regimens involving immunotherapy and chemotherapy.
Main Methods:
- Utilizing transcriptomic and histological profiling for detailed stratification of PDAC and its TME.
- Analyzing the plasticity of PDAC cells and cancer-associated fibroblasts within the TME under various treatment conditions.
- Evaluating the potential to shift the immune-cold TME towards an immune-hot phenotype.
Main Results:
- Tumor and TME stratification reveals heterogeneity and plasticity crucial for treatment response.
- Reprogramming of PDAC and stromal cells can potentially convert an immune-cold TME to an immune-hot state.
- This reprogramming may also enhance the sensitivity of PDAC to chemotherapy.
Conclusions:
- Understanding TME heterogeneity and tumor plasticity is key to advancing PDAC treatment.
- Targeting the TME offers a promising strategy to improve the efficacy of immunotherapy in PDAC.
- Combination regimens of immunotherapy and chemotherapy, informed by TME insights, may represent a future direction for PDAC management.
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