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PD-1/PD-L1 expression in pancreatic cancer and its implication in novel therapies
Adrian Mucileanu1, Romeo Chira2, Petru Adrian Mircea2
1Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
Abstract:
Pancreatic cancer is the seventh leading cause of death in developed countries and it still has a poor prognosis despite intense research in the last 20 years. Immunotherapy is a relatively new strategy in cancer treatment. The aim of immunotherapy is to block the immunosuppressive effect of tumoral cells. The PD1/PD-L1 axis has an important role in the inhibition of effector T cells and the development of regulatory T cells (Tregs). Blocking these checkpoints, and also inhibitory signals, leads to apoptosis of Tregs and increased immune response of effector T cells against tumoral antigens. Unfortunately, pancreatic cancer is generally considered to be a non-immunogenic tumor. Thus PD-1/PD-L1 inhibitors demonstrated poor results in pancreatic cancer, excepting some patients with MSI/dMMR (microsatellite instability/deficient mismatch repair). Furthermore, pancreatic cancer has a particular microenvironment with a strong desmoplastic reaction, increased interstitial fluid pressure, hypoxic conditions, and acidic extracellular pH, which promote tumorigenesis and progression of the tumor. Mismatch repair deficiency (dMMR) is correlated with a high level of mutation-associated neoantigens, most recognized by immune cells which could predict a favorable response to anti-PD-1/PD-L1 therapy. PD-1/PD-L1 molecules could be also found as soluble forms (sPD-1, sPD-L1). These molecules have a potential role in the prognosis and treatment of pancreatic cancer.
Insights
Pancreatic cancer immunotherapy shows limited success due to the tumor microenvironment. However, targeting the PD-1/PD-L1 pathway may benefit patients with mismatch repair deficiency (dMMR) by enhancing anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Pancreatic cancer has a poor prognosis, ranking as the seventh leading cause of death globally.
- Immunotherapy aims to overcome tumor-induced immunosuppression, with the PD-1/PD-L1 axis being a key target.
- Pancreatic tumors often exhibit a non-immunogenic profile and a hostile microenvironment, hindering effective immune responses.
Purpose of the Study:
- To explore the role of the PD-1/PD-L1 axis in pancreatic cancer.
- To investigate the potential of immunotherapy, particularly PD-1/PD-L1 inhibitors, in pancreatic cancer treatment.
- To understand how tumor microenvironment factors and mismatch repair deficiency influence immunotherapy outcomes.
Main Methods:
- Review of current research on pancreatic cancer immunology and immunotherapy.
- Analysis of the PD-1/PD-L1 pathway's function in T cell regulation and tumor immune evasion.
- Examination of the impact of the pancreatic tumor microenvironment (desmoplasia, pH, hypoxia) on treatment efficacy.
- Correlation of mismatch repair deficiency (dMMR) with neoantigen load and response to PD-1/PD-L1 blockade.
Main Results:
- PD-1/PD-L1 inhibitors have shown limited efficacy in pancreatic cancer, except in a subset of patients with MSI/dMMR.
- Mismatch repair deficiency (dMMR) is associated with increased neoantigens, potentially predicting a better response to anti-PD-1/PD-L1 therapy.
- The pancreatic tumor microenvironment presents significant barriers to immunotherapy, including desmoplastic stroma and altered pH.
- Soluble PD-1 and PD-L1 (sPD-1, sPD-L1) may serve as prognostic markers and therapeutic targets.
Conclusions:
- Pancreatic cancer's non-immunogenic nature and immunosuppressive microenvironment present challenges for PD-1/PD-L1 blockade.
- Mismatch repair deficiency (dMMR) represents a potential predictive biomarker for immunotherapy response in pancreatic cancer.
- Further research into overcoming the tumor microenvironment and exploring soluble PD-1/PD-L1 roles is warranted for improving pancreatic cancer immunotherapy.
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