# Quantitative assessment of pre-metastatic immune subversion as a risk factor for melanoma relapse

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $623,722

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in understanding the immunological paradox by which solid tumors first
metastasize via lymphatic channels into the immune-rich lymph node. During this process, immune
surveillance is disabled, ultimately allowing metastatic dissemination to the precise location where it should be
first eliminated—the tumor-draining, sentinel lymph node (SLN). While notably prognostic, it is clear the
metastatic status of the SLN alone is not sufficient in determining patient’s risk or relapse. Therefore,
understanding the mechanisms underlining this chronic process of tumor mediated regional
immunosuppression, commonly referred to as pre-metastatic niche (PMN) formation in the SLN will lend
significant insights for developing improved prognostic and therapeutic tools to detect and reverse cancer
dissemination early in the natural history of metastatic progression. Our long term goal is to develop
therapeutic strategies capable of overcoming the immune compromise of the SLN PMN and thereby disrupt
the first stage of cancer metastasis. Therefore, the objective of the current work is to mechanistically
interrogate the process by which the subcellular component of the primary tumor lymphatic effluent directly
mediates PMN formation. The central hypothesis proposes that in solid tumors, subcellular mediators derived
from the primary tumor microenvironment actively traffic through the lymphatics and in a cargo-dependent
manner create a PMN in the tumor-draining SLN. This hypothesis has been formulated on the basis of
preliminary data produced in the applicant’s laboratory; namely the discovery and characterization of
human lymphatic extracellular vesicles (L-EV) which have a demonstrated capacity to modulate
immune function. The rationale asserts that in elucidating the factors and signatures that define PMN
formation in the SLN, the knowledge gained will be significant as it will identify histopathologic biomarkers that
could aid in patient risk stratification beyond the presence of melanoma cells in the SLN. Guided by strong
preliminary data, this hypothesis will be tested in two specific aims: 1) identify mechanisms whereby lymphatic
subcellular factors promote immune dysfunction in the pre-metastatic SLN beyond those already identified (i.e.
S100A9); 2) evaluate the prognostic utility of these immune-modulating factors in predicting risk of recurrence
by considering the comprehensive, interactive cellular landscape that defines the immunologically
compromised SLN. The approach is innovative as it will use a mechanism-driven model to identify subcellular
factors from a previously uncharacterized biological fluid, human lymph (Aim 1), complemented by a novel,
multiplexed biomarker imaging approach in order to survey the SLN immunological landscape in a quantitative
and spatially preserved manner to ultimately translate predictive features into clinically amenable platforms
(Aim 2). Such findings will result in a ref...

## Key facts

- **NIH application ID:** 10310757
- **Project number:** 1R01CA260259-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** SVETOMIR Nenad MARKOVIC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $623,722
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310757

## Citation

> US National Institutes of Health, RePORTER application 10310757, Quantitative assessment of pre-metastatic immune subversion as a risk factor for melanoma relapse (1R01CA260259-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10310757. Licensed CC0.

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