? Overall Distant metastasis is the primary cause of cancer-related death. To colonize distant tissues, cancer cells must migrate while evading elimination by the immune system. Evidence suggests that key steps in the induction process of immune tolerance occur early in the metastatic cascade, located at regional lymph nodes. However, the nature of the interactions between tumors and immune cells remains poorly understood, particularly for those occurring within the lymph nodes. Even though lymph nodes are in fact commonly assessed in cancer patients to determine disease stage and treatment plan, they are understudied in the context of metastatic progression. To fill this scientific knowledge gap, we propose a Research Center focused on the role of lymph node metastases in tumor-mediated immunosuppression. We hypothesize that lymph node metastasis constitutes an essential, first step in the metastatic cascade of cancer progression. Based on our preliminary findings, we speculate that such metastases act locally upon the adaptive immune system within the nodes to begin to induce systemic tolerance of the tumor. We will explore, compare and test this hypothesis in two malignancies: (i) melanoma and (ii) head and neck squamous cell carcinoma. We have assembled a multidisciplinary team whose coordinated efforts will involve the application of genomic and single-cell in-situ imaging technologies on preclinical and human samples to explore the evidence and mechanisms of the induction of immunosuppression in the lymph nodes. We propose three inter-connected Research Projects that focus our scientific theme on different platforms: murine models (Project 1), high-dimensional in-situ imaging (Project 2), and integrative computational analysis (Project 3). All three projects will utilize a shared resource core dedicated to the acquisition of patient samples and associated clinical annotation and data management (Biospecimen and Data Management Core. These efforts will yield highly multiplexed, multi-scale datasets which will be analyzed by novel bio-computational methods to reconstruct intracellular and intercellular molecular interaction networks in order to identify, then functionally validate, critical mediators of tumor immunosuppression. Our ultimate objective is to advance our understanding of the systemic consequences of lymph node metastases and identify new therapeutic approaches to cancer immunotherapy. Our Research Center is also dedicated to promoting our early investigators as the next generation thought leaders in cancer systems biology. Our Outreach Core will ensure that our Research Center's scientific and methodological advances in applying the principles of cancer systems biology toward the study of tumor- immune interactions are fully disseminated in the cancer research and broader communities.

Public Health Relevance

? Overall Metastasis of tumor cells from the primary to distant sites is the primary cause of cancer-related death. The immune system is a key gatekeeper that metastatic cells must circumvent in order to colonize at distant sites. Our Research Center aims to identify the mechanisms in which tumor cells instruct the immune system to tolerant them by focusing on the understudied role of lymph node invasion in tumor-mediated immunosuppression. Our findings promise to provide critical insights into blocking metastatic progression and thereby preventing cancer-related deaths.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54CA209971-01
Application #
9186170
Study Section
Special Emphasis Panel (ZCA1-RTRB-R (M1))
Program Officer
Hughes, Shannon
Project Start
2016-08-25
Project End
2021-07-31
Budget Start
2016-08-25
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
$1,970,671
Indirect Cost
$727,258
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Spitzer, Matthew H; Carmi, Yaron; Reticker-Flynn, Nathan E et al. (2017) Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell 168:487-502.e15
Kenkel, Justin A; Tseng, William W; Davidson, Matthew G et al. (2017) An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer. Cancer Res 77:4158-4170
Bhattacharya, Nupur; Yuan, Robert; Prestwood, Tyler R et al. (2016) Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer. Immunity 45:641-655