Author ORCID Identifier

https://orcid.org/0000-0002-6503-6851

Date of Graduation

5-2021

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Raghu Kalluri

Committee Member

Huamin Wang

Committee Member

Florencia McAllister

Committee Member

Robert Jenq

Committee Member

Jennifer Wargo

Abstract

The Functional Contribution Of Adaptive Immunity In The Biology Of Pancreatic Cancer And Therapeutic Targeting Of Oncogenic Kras

Krishnan K. Mahadevan M.B.B.S*

Advisory professor: Dr. Raghu Kalluri

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the USA(https://seer.cancer.gov/statfacts/html/pancreas.html), whereby survival remains poor despite advances in surgical technique and new combination chemotherapies. Immune checkpoint blockade has revolutionized the treatment of cancers such as melanoma, bladder cancer and non-small cell lung carcinomas. Unfortunately, PDAC is among the tumor types that remain refractory to checkpoint immunotherapy(Royal et al., 2010, Le et al., 2013), with no survival benefits in clinical trials and pre-clinical animal models of PDAC(Winograd et al., 2015). Failure to respond to checkpoint blockade is frequently attributed to an immunosuppressive tumor microenvironment (TME), low neo-epitope burden and lack of tumor infiltrating T cells resulting from a desmoplastic stroma(McAllister et al., 2014, Zhang et al., 2014). However, the molecular underpinnings of immunosuppression in PDAC remain poorly understood.

Oncogenic Kras (Kras*, KrasG12Dand other mutations), a key driver of PDAC is thought to play an important role in creating an immunosuppressive TME(Zhang et al., 2014, McAllister et al., 2014); however, its precise function in shaping the immune landscape of PDAC remains elusive. There is no clear understanding of the functional contribution of T cells and the nodes of regulation of immune infiltration in PDAC. In order to exploit the full potential of the immune system to treat PDAC, it is urgent to generate in vivomodels that enables us functionally probe the role of oncogenic Kras in shaping the TME with an inducible and pancreas specific model expressing Kras*. We demonstrate that Kras* contributed to a T cell deficient and myeloprofilerative TME in PDAC. Next, we generate models that closely mimic human PDAC and allow depletion of specific T cell subsets (CD4 and CD8+T cells). Such models offer a unique modality to interrogate the role of specific T cell subsets in PDAC progression and inform the development of effective immunotherapy approaches for PDAC. We employ a Kras* targeting agent (iExosomes) in the T cell depletion models to demonstrate that combination of Kras* and CD4+T cell targeting strategies resulted in robust tumor growth inhibitory response. Further, we show how the gut microbiome modulates T cell responses in the context of Kras* targeting in PDAC.

In the second part of our study, we determine how the presence of pancreatitis alters the TME and the course of progression of PDAC. A significant portion of PDAC patients have been reported to present with underlying chronic pancreatitis and bile duct obstruction. However, current therapeutic strategies do not consider the influence of chronic pancreatitis while stratifying PDAC patients in clinical trials. The presence of chronic inflammation in a cancer setting could recruit a unique immune signature to the TME and open new possibilities for immune modulation in these PDAC patients. Therefore, we investigate how pancreatitis impacts tumor progression and modulates the immune landscape of the PDAC microenvironment. We demonstrate that pancreatitis accelerates tumorigenesis in mice with Kras* mutant pancreas and recruits activated dendritic cells to the tumor microenvironment. However, CD4+T cells promote pancreatic tumorigenesis in mice with pancreatitis by regulating dendritic cells in the TME. Further, we demonstrate that presence of pancreatitis sensitizes the pancreatic immune microenvironment to checkpoint blockade.

Overall, our study offers novel mechanistic insights into how Kras* modulates the immune microenvironment andunravels potential therapeutic windows to synergize Kras* and CD4+T cell targeting approaches. Further, our study offers insights into how presence of pancreatitis alters immune microenvironment, suggesting stratification of a cohort of patients in clinical trials that could potentially benefit from immunotherapy approaches.

Keywords

Pancreatic cancer, dendritic cells, immunology

Available for download on Saturday, May 07, 2022

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