# Investigating the tumor-immune interactome in metastases

> **NIH NIH F99** · YALE UNIVERSITY · 2021 · $47,536

## Abstract

PROJECT SUMMARY
 The progression of transformed primary tumors to metastatic colonization is a lethal determinant of disease
outcome. While the immune system actively engages with metastatic cells in both supportive and limiting roles,
the functional consequence of the tumor – immune interactome (the entirety of interactions between immune
cells and tumor cells) during metastatic disease remains ill defined.
 In the F99 portion of this proposal we will examine how local immune cells orchestrate host anti-metastatic
immunity. While circulating adaptive and innate lymphocyte effector responses are required for effective anti-
metastatic immunity, whether tissue resident immune circuits confer initial immunity at sites of metastatic
dissemination remains to be elucidated. Using a syngeneic mouse melanoma model, we have demonstrated
that lung resident conventional type 2 dendritic cells (DC2) orchestrate local immune circuits to confer initial
host anti-metastatic immunity. Specific ablation of lung DC2, and not peripheral DC populations, led to
increased metastatic burden in the presence of an intact T cell and NK cell compartment. Critically, DC2 serve
as a robust source of proinflammatory cytokines that directs the essential local production of IFN- by lung
resident NK cells. Collectively our results highlight a novel DC2 - NK cell axis that colocalizes around
pioneering metastatic cells in order to orchestrate a non-redundant innate immune response program to limit
initial metastatic burden in the lung. In Aim 1 we will explore the signals that activate DC2 controlled immune
circuits and elucidate the mechanism that instruct both immediate and long term adaptive anti-metastatic
immunity. Ultimately, we will look to see how we can leverage this knowledge to potentiate host-anti-metastatic
responses in immune refractory tumors.
 In the K00 phase of this proposal, I propose to extend my research of investigating immune interactions
during metastasis by developing a novel in vivo tool to discover and record the tumor-immune interactome.
The ability of immune cells to directly interact with transformed cell is an essential component of immune
surveillance of the tissue and critical for optimal function. However, the nature and consequence of immune
surveillance in the metastatic microenvironment remains unclear. Current tools are limited in their ability to
faithfully record and discover novel interactors in vivo. In Aim 2, we plan to develop, validate, and apply a novel
technology to discover and record the tumor immune interactome in an unbiased way using Synthetic Notch
receptors. This system, which we call Tumor Immune Interactome Non-biased Discovery Reporter (TIINDR),
will allow us to interrogate immune interactors and non-interactors in metastatic tumor models in order to
understand that nature and consequence of metastatic immunosurveillance.
 Collectively, this proposed research will provide insights into the mechanism of immune surveillance...

## Key facts

- **NIH application ID:** 10305285
- **Project number:** 1F99CA264425-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Orr-El Weizman
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,536
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305285

## Citation

> US National Institutes of Health, RePORTER application 10305285, Investigating the tumor-immune interactome in metastases (1F99CA264425-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10305285. Licensed CC0.

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