Dynamic Immune and Stromal Modulation by Therapeutic Targeting of IL-6 in Pancreatic Cancer 公开
Ware, Michael (Fall 2020)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. This cancer progresses silently in early stages, resulting in many patients presenting with metastatic disease. The aggressive and inherit drug resistant nature of PDAC is heavily influenced by the unique fibrotic stroma of PDAC, sometimes comprising up to 90% of the tumor by volume. This stroma contains dense matrices of collagen and fibronectin which harbor immune suppressive myeloid cells, regulatory T-lymphocytes and cancer associated fibroblasts (CAFs). Our research has revealed the highly heterogeneous populations of CAFs in PDAC to be key mediators of disease progression. Specifically, we previously identified interleukin-6 (IL-6) to be the most highly transcribed soluble factor by these cells, driving suppressive myeloid cells expansion while blunting T-cell responses to PDAC. Here, my thesis research sought to expand our knowledge of CAFs in PDAC by investigating the role of these cells in metastasis of pancreatic cancer. I hypothesized that IL-6 secreting CAFs are essential to pancreatic cancer cells, not only governing the TME of the primary tumor, but also mediating establishment of metastatic PDAC lesions in the liver. I chose to pursue this hypothesis through two projects. First, to understand how these cells enable metastasis, and seeking to unveil novel therapeutic targets for the treatment of late stage pancreatic cancer. I found PDAC associated CAFs to promote pancreatic cancer spheroid invasion through production of soluble factors and when in co-culture with tumor cells. Our lab previously utilized murine models of PDAC, and demonstrated IL-6 blockade significantly enhanced PD-1/PD-L1 blockade therapy. Therefore, my second project sought to leverage IL-6 blockade to disrupt dynamic interactions between IL-6 secreting CAFs and tumor cells to enhance CTLA-4 blockade efficacy in PDAC. Herein, I describe mechanisms by which this therapeutic combination elicits a potent anti-tumor response dependent upon CD4+ T cells and CXCR3 which is unique to this strategy. The data I present here has the potential for future and immediate clinical translation for the benefit of patients with PDAC.
Table of Contents
Chapter 1: Biological Basis of Pancreatic Cancer .........................................................................................1
1.1 Author’s Contributions and Acknowledgement of Reproduction. ............................................................ 1
1.2 Pancreatic Cancer. ...............................................................................................................................1
1.3 Key biologic properties and mutations of relevance to pancreatic cancer. ................................................ 6
1.4 The stroma is a unique feature of the microenvironment in pancreatic cancer....................................... ..11
1.5 Controversial role of the stroma in the pancreatic disease process ......................................................... 12
1.6 Tumor Associated Inflammation Controls Local and Systemic Immunity in PDAC. ............................ ......19
1.7 Targeting dominant pathways in the tumor microenvironment. ............................................................. 20
1.8 Scope and Goals for this Project. ...........................................................................................................22
Chapter 2: Metastatic Spread of PDAC is Supported by Fibroblasts ...................................................... .........25
2. 1 Introduction. ......................................................................................................................................25
2.2 Methods. .............................................................................................................................................28
2.3 Results. ...............................................................................................................................................31
2.4 Discussion. ..........................................................................................................................................48
Chapter 3: Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T-cell-dependent manner. ......................................................................................................................................... .......................58
3.1. Author’s Contribution and Acknowledgement of Reproduction. ............................................................. 58
3.2. Abstract. ............................................................................................................................................ 59
3.3 Introduction. .......................................................................................................................................60
3.4 Results. ................................................................................................................................................61
3.5 Discussion. ...........................................................................................................................................86
3.6. Author’s Contribution and Acknowledgement of Reproduction .......................................................... .....90
Chapter 4: Conclusions and Closing Remarks ..................................................................................... ..........95
4.1 Future Studies. ..................................................................................................................................... 95
4.2 Concluding Remarks. .............................................................................................................................95
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