Pancreatic Ductal Adenocarcinoma: A Review of Immunologic Aspects

Wachsmann, Megan B.; Pop, Laurentiu M.; Vitetta, Ellen S.

doi:10.2310/jim.0b013e31824a4d79

Cited by 50 publications

(33 citation statements)

References 289 publications

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“…It has been reported that PDA typically has few TILs, whereas the lymphocytic populations are predominantly found in the stroma surrounding the tumor mass (33), and recent studies suggest that the T cells in long-term survivors with pancreatic cancer target neoantigens (34). The presence of high numbers of TILs and extensive infiltration are major indicators of favorable patient prognosis and positive therapeutic responses in treating several solid tumors, including colorectal cancer (35), lung cancer (36), and ovarian carcinomas (37,38).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

Watanabe¹,

Luo²,

Da³

et al. 2018

JCI Insight

219

163

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Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA.

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Section: Discussionmentioning

confidence: 99%

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

Watanabe¹,

Luo²,

Da³

et al. 2018

JCI Insight

219

163

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“…Professional antigen presenting cells (APC) such as dendritic cells (DC) and macrophages play a pivotal role in tumorigenesis and in the complex microenvironment of pancreatic cancer and periampullary adenocarcinomas [2]. Tumour associated macrophages (TAM) can roughly be divided into two subtypes, M1 and M2, whereof M1 are associated with pro-inflammatory properties and M2 anti-inflammatory properties.…”

Section: Introductionmentioning

confidence: 99%

The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype

et al. 2017

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BackgroundDendritic cells (DC) and tumour-associated macrophages (TAM) are essential in linking the innate and adaptive immune response against tumour cells and tumour progression. These cells are also potential target for immunotherapy as well as providing a handle to investigate immune status in the tumour microenvironment. The aim of the present study was to examine their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological subtype.MethodsThe density of tolerogenic immature CD1a+ dendritic cells (DC), and MARCO+, CD68+ and CD163+ tissue-associated macrophages (TAM) was analysed by immunohistochemistry in tissue micro arrays with tumours from 175 consecutive cases of periampullary adenocarcinoma who had undergone pancreaticoduodenectomy, 110 with pancreatobiliary type (PB-type) and 65 with intestinal type (I-type) morphology. Kaplan–Meier and Cox regression analyses were applied to determine the impact of immune cell infiltration on 5-year overall survival (OS).ResultsHigh density of CD1a+ DCs was an independent prognostic factor for a reduced OS in PB-type but not in I-type tumours (adjusted HR = 2.35; 95% CI 1.13–4.87). High density of CD68+ and CD163+ TAM was significantly associated with poor OS in the whole cohort, however only in unadjusted analysis (HR = 1.67; 95% CI 1.06–2.63, and HR = 1.84; 95% CI 1.09–3.09, respectively) and not in strata according to morphological subtype. High density of MARCO+ macrophages was significantly associated with poor prognosis in I-type but not in PB-type tumours (HR = 2.14 95% CI 1.03–4.44), and this association was only evident in patients treated with adjuvant chemotherapy. The prognostic value of the other investigated immune cells did not differ significantly in strata according to adjuvant chemotherapy.ConclusionsThe results from this study demonstrate that high infiltration of tolerogenic immature DCs independently predicts a shorter survival in patients with PB-type periampullary adenocarcinoma, and that high density of the MARCO+ subtype of TAMs predicts a shorter survival in patients with I-type tumours. These results emphasise the importance of taking morphological subtype into account in biomarker studies related to periampullary cancer, and indicate that therapies targeting dendritic cells may be of value in the treatment of PB-type tumours, which are associated with the worst prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1256-y) contains supplementary material, which is available to authorized users.

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“…PDAC develops by an adenoma to carcinoma sequence as a result of accumulating genetic alterations, which provide signals (e.g. TGFβ via SMAD4) that promote recruitment of immune cells [8, 80, 89]. Histologically, microscopic pancreatic intraepithelial neoplasms (PanIN) progress from intraepithelial to invasive pancreatic cancer and parallel the accumulating genetic alterations in the adenoma to carcinoma succession of PDAC [8, 33, 50].…”

Section: Introductionmentioning

confidence: 99%

Macrophages and pancreatic ductal adenocarcinoma

2016

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Monocytes and macrophages make up part of the innate immune system and provide one of the first defenses against variety of treats. Macrophages can also modulate the adaptive immune system. Efficient sensing and response to tissue environmental cues highlights the complexity and dynamic nature of macrophages and their plasticity. Macrophages may have divergent roles depending on their polarity and stimulus received. Accumulating evidence demonstrates the critical role played by macrophages in tumor initiation, development, and progression. In this review, we discuss the characteristics of tumor-associated macrophages (TAMs) and their role in pancreatic adenocarcinoma. In addition, we give an overview on recent advances related to the therapeutic implication associated with targeting TAMs in pancreas cancer.

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Pancreatic Ductal Adenocarcinoma: A Review of Immunologic Aspects

Cited by 50 publications

References 289 publications

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype

Macrophages and pancreatic ductal adenocarcinoma

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