DeNardo Lab

General Interests of the Lab:

In general, my laboratory looks at understanding how immune responses shape and are shaped by malignancies. Where possible, our hope is to exploit these weaknesses to improve patient outcomes by enhancing response to conventional, targeted or immunotherapeutics.  At current the laboratory focuses primarily on pancreas, lung and breast cancers.  The laboratory interests and project span from fundamental basic science studies to translational research and involvement in ongoing clinical trials.

Specific research areas are described below:

1) Understanding the impact of fibrosis on tumor immunity and responses to immunotherapy.

Overall: The prognosis for pancreatic cancer (PDAC) and Lung Cancer (LUAD) patients is dismal. The application of immunotherapy holds the promise to revolutionize patient outcomes. Unfortunately, attempts at immunotherapy in PDAC, to date, have not achieved significant clinical benefits as single agents. And in LUAD not all patient benifitThis is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most pancreatic ductal PDAC. Two major drivers of this tumor protective microenvironment include a dense fibrotic tumor stroma and robust infiltration by tumor-supportive myeloid cells. High stromal density provides a barrier to T cell infiltration and function. These data suggest that we could improve PDAC and LUAD patient outcomes, if we could identify therapeutics that reprogram the protective TME to facilitate immunotherapy. Approaches to this include both directly targeting the fibrotic TME and/or targeting the oncogenic signaling in malignant cells that drives these TMEs. 

Recent Example:  Recently, we have identified focal adhesion kinase (FAK)-1, which is hyper-activated as a major driver of the fibrotic and inflammatory (fibro-inflammatory) TME of PDAC tumors. We have discovered that in human PDAC, elevated FAK activity correlates with higher fibrosis levels, excessive myeloid cell infiltration, and poor T cell responses. These data suggest that FAK is a key mediator of the fibro-inflammatory microenvironment that blocks immunotherapeutic efficacy. FAK inhibition dramatically reduced fibrosis and inflammatory myeloid cell infiltration, and improved T cell function in PDAC mouse models. These findings have lead to several basic science finding and ongoing clinical trials.

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2) Understanding the differential effects of macrophage subsets and origin on tumor fibrosis, immunity and metastatic progression.

Example Project: Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we systemically investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas resident macrophages originate during embryonic development and expand through in situ proliferation during tumor progression. While monocyte-derived TAMs play more potent roles in antigen presentation, embryonically derived TAMs exhibit a pro-fibrotic transcriptional profile suggesting their role in producing and remodeling extracellular matrix molecules. Collectively, these findings uncovered the heterogeneity of TAM origin and functions, and could provide therapeutic insight for PDAC treatment.

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3) Understanding the impact of Dendritic Cell and Macrophages on Tumor Immunity and Response to Immunotherapy.

Example Project:  Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

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4) Ongoing "Newer" Areas of Basic/Translational Research

1. Organ Specific Differences in Immune and Stromal Response to Metastasis

2. The Role of Stromal Senescence in Tumor Immunology and Disease Progression 

3. The Impact of Standard of Care Radiation and Chemotherapy on Tumor and Stromal Adaptation. 

5) Building Collaborative Translational Teams in Pancreatic Cancer

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