CCSB Summary

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.

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.

Hypothesis

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.

Objective

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 findings promise to provide critical insights into blocking metastatic progression and thereby preventing cancer-related deaths.

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