# Project 1: Murine Modeling of Tumor-Mediated Immunosuppression

> **NIH NIH U54** · STANFORD UNIVERSITY · 2020 · $377,697

## Abstract

ABSTRACT/SUMMARY - Project 1: Murine Modeling of Tumor-Mediated Immunosuppression
Like many tumors, melanoma and head and neck squamous cell carcinoma (HNSCC) often metastasize first to
regional lymph nodes, and patients with such metastases typically have poor prognoses. It remains unclear
why lymph nodes, with their capacity to recognize distinctive antigens such as those produced by tumors,
would be hospitable for metastatic outgrowth of the primary tumor. Previous studies of other cancers have
identified mediators of tissue-specific metastases to sites such as the lungs, bone, and brain. However, most of
these studies have utilized immunodeficient mice and thus have not queried the role of the adaptive immune
response in inhibiting or facilitating spread to those tissues. We hypothesize that lymph node metastasis
constitutes an essential first step in the metastatic cascade of melanomas and HNSCC in that such
metastases act locally upon the adaptive immune system within the lymph nodes to induce tolerance
to the tumor and that leukocytes recirculating from these nodes carry the tolerance to distant sites.
Our objectives are to establish whether lymph node metastases induce perturbations in anti-tumor immunity
and to identify the mechanisms of these perturbations. Starting with murine models, then validating in human
tissue, we will a) characterize differences in local and systemic immune responses to metastatic tumors; b)
identify differential regulators of tolerance induction by metastatic cells through the use of genomic profiling;
and c) identify the molecular mediators of metastatic tolerance induction. Through the use of serial in vivo
passaging in a murine model, we have already developed a panel of syngeneic melanoma cell lines that
exhibit enhanced lymph node metastatic potential and will create similar lines in HNSCC. We will compare the
activation states of these immune cells, cytokine profiles, T cell polarization, and cytolytic activity toward tumor
cells using single cell proteomic methods, in partnership with Project 2. Using cytokine profiling and RNA
sequencing on the lines, we will apply computational systems biology approaches, in partnership with Project
3, to identify the molecules relevant for induction of tolerance. Samples collected by the Biospecimen and
Data Management Core will be used to corroborate our findings in human tissue. If our hypothesis is proven
correct that lymph node metastasis is an obligate step in the generation of systemic disease due to tolerance
induction, targeting the molecules responsible for lymph node metastasis induced tolerance could prevent and
treat metastatic disease.

## Key facts

- **NIH application ID:** 9982081
- **Project number:** 5U54CA209971-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** EDGAR G. ENGLEMAN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,697
- **Award type:** 5
- **Project period:** — → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982081

## Citation

> US National Institutes of Health, RePORTER application 9982081, Project 1: Murine Modeling of Tumor-Mediated Immunosuppression (5U54CA209971-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9982081. Licensed CC0.

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