# Deciphering the molecular control of intratumoral dendritic cells

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $548,745

## Abstract

PROJECT SUMMARY
 Dendritic cells (DC) have a major influence on tumor immunity. DC depletion abrogates tumor immunity and
response to PD1 (αPD1) immunotherapy in many preclinical tumor models and DC infiltration in human tumors
is a positive correlate of clinical outcome. Unfortunately, we still lack effective strategies for harnessing DC to
stimulate tumor immunity and this is in large part because we do not fully understand the control of tumor DCs.
 To address this shortcoming, we performed scRNA-seq on human and mouse lung tumor lesions. Notably,
we identified a distinct and nearly identical population of DC in both human and mouse lung tumors which
upregulated genes associated with both DC maturation such as CD40 & IL12, and immunoregulation, including
PD-L1 & CD200. This led us to annotate the cluster “mature DC enriched in immuno-regulatory molecules”
(mregDC)(Maier et al. Nature 2020). Strikingly, mregDC were the DC carrying tumor antigen (Ag); meaning these
DC are responsible for tumor Ag presentation. We hypothesize the immunostimulatory potential of tumor DC is
dampened by genes upregulated in the mreg module and this thwarts induction of tumor immunity and response
to αPD1. We propose that by targeting specific mreg genes we can decouple regulatory & stimulatory programs
and enhance DC activation of tumor-reactive T cells and promote tumor immunity and αPD1 response. In support
of our hypothesis, blocking signaling of IL4R, one of the upregulated genes in the mreg module, enhanced DC
activation, expanded tumor-infiltrating T cells, and reduced tumor burden in a mouse model of NSCLC.
Additionally, inhibition of Birc2/3, also upregulated in mregDC, led to substantially enhanced DC activation.
 To test our hypotheses and reach our objective, we will: (1) Determine the role of IL4R on induction of the
mregDC state and tumor immunity. We will knockout IL4R in mouse & human DC and determine how this
impacts mreg induction, Ag presentation, & tumor immunity. We will also combine anti-IL4R & anti-PD1 to assess
synergy in controlling tumor growth in a preclinical model. (2) Evaluate Birc2/3 inhibition on the physiology,
molecular state and immunostimulatory activity of intratumoral DC. We will test the hypothesis that
pharmacological inhibition of Birc2/3 will enhance DC production of IL-12, as well co-stimulatory molecules, while
facilitating cancer cell death and tumor Ag uptake, and result in robust tumor immunity. (3) Deconvolute the
intrinsic regulators of DC phenotype and the mreg gene module. We will utilize a first-of-its-kind CRISPR
genomics platform we developed to KO each of the 37 transcriptional related factor (TrF) genes upregulated by
mregDC and determine how each impacts tumor DC activation and molecular state. The outcome of this project
will provide a major advance in our understanding of intratumoral DC biology by determining the role of specific
genes and pathways in dampening tumor DC functions, establish in preclinical mo...

## Key facts

- **NIH application ID:** 10142805
- **Project number:** 1R01CA257195-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Brian D Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $548,745
- **Award type:** 1
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142805

## Citation

> US National Institutes of Health, RePORTER application 10142805, Deciphering the molecular control of intratumoral dendritic cells (1R01CA257195-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10142805. Licensed CC0.

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