Tumor progression is characterized by the spread of cancer cells from the primary site to regional lymph nodes and distant organs. In order to colonize distant sites, cancer cells must acquire invasive capacity, while evading elimination by immune cells. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with the lowest survival rate of all solid tumors. PDAC shares many histological and molecular features with distal cholangiocarcinoma (dCCA), which is a biliary tract cancer usually located in the head of the pancreas albeit showing better prognosis than PDAC. Lymph node metastases (LNM) represent an immunological meeting place for tumor cells and components of the adaptive immunity. Moreover, the pathological N-status (presence and number of LNM) is superior to the T-status (size of the tumor) in predicting survival of PDAC and dCCA patients. However, the biological role of LNM in tumor progression remains undefined. Here, using patient-derived organoids (PDOs) established from matched primary tumor (TP-PDOs) and LNM (LN-PDOs) of 5 patients, we show that both TP- and LN-PDOs shared the histological features and immunophenotypes of parental tissues. Comparative whole-exome sequencing of paired TP- and LN-PDOs showed substantial genetic conservation when considering functional driver genes. Moreover, LN-PDOs did not exhibit increased tumorigenic and/or metastatic capacity in vivo compared to matched TP-PDOs. On the other hand, transcriptional profiles of the cultures showed an overrepresentation of immune-related programs in LN-PDOs and ex vivo experiments demonstrated an elevated immunosuppressive activity of LN-PDOs towards human T lymphocytes. Mechanistically, we found that the mitochondrial form of arginase (ARG2), which catalyzes the hydrolysis of L-arginine to L-ornithine and urea, is overexpressed in LN-PDOs compared to matched TP-PDOs and, accordingly, the addition of exogenous L-arginine partially rescued the suppressive effect of LN-PDOs on T lymphocytes. Taken together, our data show that LNM are able to inhibit T lymphocytes proliferation potentially through arginine depletion, and this may contribute to systemic immunosuppression in these diseases.

Unraveling the role of lymph node metastasis in PDAC and dCCA progression

Fiorini Elena;Delfino Pietro;D’Agosto Sabrina;Andreani Silvia;Adamo Annalisa;Pezzini Francesco;Frusteri Cristina;Canè Stefania;Rusev Borislav;Maggino Laura;Malleo Giuseppe;Bronte Vincenzo;Bassi Claudio;Scarpa Aldo;Ugel Stefano;Carbone Carmine;Corbo Vincenzo
2021

Abstract

Tumor progression is characterized by the spread of cancer cells from the primary site to regional lymph nodes and distant organs. In order to colonize distant sites, cancer cells must acquire invasive capacity, while evading elimination by immune cells. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with the lowest survival rate of all solid tumors. PDAC shares many histological and molecular features with distal cholangiocarcinoma (dCCA), which is a biliary tract cancer usually located in the head of the pancreas albeit showing better prognosis than PDAC. Lymph node metastases (LNM) represent an immunological meeting place for tumor cells and components of the adaptive immunity. Moreover, the pathological N-status (presence and number of LNM) is superior to the T-status (size of the tumor) in predicting survival of PDAC and dCCA patients. However, the biological role of LNM in tumor progression remains undefined. Here, using patient-derived organoids (PDOs) established from matched primary tumor (TP-PDOs) and LNM (LN-PDOs) of 5 patients, we show that both TP- and LN-PDOs shared the histological features and immunophenotypes of parental tissues. Comparative whole-exome sequencing of paired TP- and LN-PDOs showed substantial genetic conservation when considering functional driver genes. Moreover, LN-PDOs did not exhibit increased tumorigenic and/or metastatic capacity in vivo compared to matched TP-PDOs. On the other hand, transcriptional profiles of the cultures showed an overrepresentation of immune-related programs in LN-PDOs and ex vivo experiments demonstrated an elevated immunosuppressive activity of LN-PDOs towards human T lymphocytes. Mechanistically, we found that the mitochondrial form of arginase (ARG2), which catalyzes the hydrolysis of L-arginine to L-ornithine and urea, is overexpressed in LN-PDOs compared to matched TP-PDOs and, accordingly, the addition of exogenous L-arginine partially rescued the suppressive effect of LN-PDOs on T lymphocytes. Taken together, our data show that LNM are able to inhibit T lymphocytes proliferation potentially through arginine depletion, and this may contribute to systemic immunosuppression in these diseases.
lymph node metastasis, tumor progression, organoids, PDAC, distal cholangiocarcinoma
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Descrizione: PhD thesis Fiorini Elena
Tipologia: Tesi di dottorato
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1045180
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