Dataset Information

Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma.

ABSTRACT:

Purpose

Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.

Experimental design

PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations.

Results

We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets.

Conclusions

Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.

SUBMITTER: Piper M

PROVIDER: S-EPMC8898296 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma.

Piper Miles M Van Court Benjamin B Mueller Adam A Watanabe Shuichi S Bickett Thomas T Bhatia Shilpa S Darragh Laurel B LB Mayeda Max M Nguyen Diemmy D Gadwa Jacob J Knitz Michael M Corbo Sophia S Morgan Rustain R Lee Jung-Jae JJ Dent Alexander A Goodman Karyn K Messersmith Wells W Schulick Richard R Del Chiaro Marco M Zhu Yuwen Y Kedl Ross M RM Lenz Laurel L Karam Sana D SD

Clinical cancer research : an official journal of the American Association for Cancer Research 20220301 5

<h4>Purpose</h4>Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.<h4>Experimental design</h4>PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in comb ...[more]

PMID: 34862244

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome. However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumor-associated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.MethodsGene profiles for NLRP3 (+/+) and NLRP3 (-/-) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (-/-) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.ResultsGEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.ConclusionsOur results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic carcinomas. Prognosis is poor with a worldwide five-year survival rate of 2-9%. Extent of metastasis is a prognostic factor. Most common metastatic sites include the liver, peritoneum, lung, and bones. We report a case of distant metastasis of PDAC to the left choroid.Case descriptionThis patient is a 59-year-old Caucasian male who initially presented with right flank pain progressing to exercise and activity impairment. Abdominal computed tomography scan showed a pancreatic tail mass subsequently confirmed as PDAC via endoscopic ultrasound with fine needle aspiration. Prior to treatment initiation, patient was referred to ophthalmology for acute vision changes. Evaluation revealed left eye pigmentary changes overlying subretinal fluid (SRF) along with peripheral retinal depigmentation indicative of choroidal metastasis. As of this report submission, patient has completed his initial 6-month course of gemcitabine/paclitaxel protein-bound/cisplatin with partial response. He remains active on his second line of chemotherapy. Visual disturbances and evidence of choroidal metastasis continue to resolve.ConclusionsPDAC is often identified at a late stage, with metastasis or local advancement identified in 80-85% of first diagnoses. This is thought to account for its poor median survival of two to eleven months. The retinal choroid is an extremely rare site of PDAC metastasis, with less than ten cases reported in literature. In this patient, the choroid was the first confirmed metastatic site and represented distant metastasis. Nevertheless, this patient continues to do well and is expected to exceed the upper bound median survival of 11 months following systemic chemotherapy. From this case, we note that distant metastasis prior to treatment initiation may not predict worse prognosis. Systemic chemotherapy was effective in both primary tumor shrinkage as well as regression of choroidal metastasis, leading to improvement in visual symptoms. This suggests that while choroidal metastasis should not be missed in patients with PDAC, systemic chemotherapy may be effective in mitigating collateral symptomatology and thus preserving quality of life.

Dataset Information

Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma.

Purpose

Experimental design

Results

Conclusions

Publications

Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma.

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