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Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.

ABSTRACT: Neoadjuvant chemotherapy (NAC) is often the treatment of choice for borderline resectable and locally advanced invasive pancreatic ductal adenocarcinoma (PDAC); however, most cancers only partially respond to therapy. We hypothesized that the location of residual neoplastic cells in resected specimens following NAC could provide a clue as to the mechanisms of resistance. PDAC cells invade the stroma but can also invade back into and spread via the pancreatic ducts, which has been referred to as "cancerization of ducts" (COD). We compared the responsiveness to chemotherapy between PDAC cells in the stroma and PDAC cells in the duct. Pancreatic resections from a total of 174 PDAC patients (NAC, n?=?97; immediate surgery, n?=?77) were reviewed. On hematoxylin and eosin sections, COD was identified at the same prevalence in both groups (NAC: 50/97 cases, 52%; immediate surgery: 39/77 cases, 51%; p?=?0.879, Fisher's exact test). However, using quantitative image analysis of CK19 immunohistochemistry, we found that the proportion of cancer cells that were intraductal was significantly different between the NAC and immediate surgery groups (median; 12.7% vs. 1.99%, p?

SUBMITTER: Fujikura K

PROVIDER: S-EPMC7529702 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.

Fujikura Kohei K Hutchings Danielle D Braxton Alicia M AM Zhu Qingfeng Q Laheru Daniel A DA Hruban Ralph H RH Thompson Elizabeth D ED Wood Laura D LD

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20200526 10

Neoadjuvant chemotherapy (NAC) is often the treatment of choice for borderline resectable and locally advanced invasive pancreatic ductal adenocarcinoma (PDAC); however, most cancers only partially respond to therapy. We hypothesized that the location of residual neoplastic cells in resected specimens following NAC could provide a clue as to the mechanisms of resistance. PDAC cells invade the stroma but can also invade back into and spread via the pancreatic ducts, which has been referred to as ...[more]

PMID: 32457408

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Project description:Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the "nest" could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma. Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model. Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model. Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.

Project description:BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%-40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODSWe performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTSIn human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSIONNeoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDINGThis work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.

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Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.

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Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy.

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