# Identification of Novel Gene Regulatory Interactions Driving the Immune Evasion Program Through Transcriptional Activation of CD47 in Cancer

> **NIH NIH K22** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $199,098

## Abstract

ABSTRACT: CD47 is a cell surface protein, found virtually in every cell, which interacts with SIRPα on
macrophages to inhibit phagocytosis. In cancer cells, CD47 transcript and protein expression is aberrantly
upregulated, protecting the cancer cells from being recognized and cleared by macrophages. Blockade of
CD47-SIRPα signaling by anti-CD47 or anti-SIRPα monoclonal antibodies (mAbs) enhances macrophage
phagocytosis of a variety of cancer types. Due to the clinical implications this information has, it is critical
to understand the precise mechanisms and upstream regulators responsible for increasing CD47
expression in cancer cells, to develop novel therapies to target the upstream group of transcription
factors, genetic or epigenetic modifications that misregulate CD47 in leukemia and solid tumors, and in
this manner, prevent malignant cells from evading immunosurveillance. By performing a genomic cis-
regulatory analysis, I found that two distinct super-enhancers (SEs) are associated with CD47 in certain cancer
cell types and not in their healthy counterparts. I also found that a set of active constituent enhancers, located
within each of the two CD47 SEs, regulate CD47 expression in different cancer cell types: while 1) an
upstream CD47 constituent enhancer is active in T-cell lymphoblastic leukemia (T-ALL) cells, 2) a downstream
CD47 constituent enhancer is active in breast cancer (hormone-positive subtype), and it responds to induction
of the TNF–NFKB1 signaling pathway. In contrast, my preliminary data suggests that CD47 upregulation in
leukemia cell lines, is independent of this inflammatory pathway, and is dependent on pathways that are involved
in hematopoietic developmental processes. Based on these findings, I hypothesize that: in different cancer
types, uniquely formed distal enhancers or super-enhancers (SEs), recruit inputs (transcription factors) from the
inflammatory and/or developmental program to dysregulate target genes of immune evasion (e.g, CD47). This
proposal aims to investigate other mechanisms (including epigenetic changes and genomic modifications) that
alone or in combination with the TNF inflammatory pathway are used particularly by breast cancer cells and
leukemia subtypes to initiate an immune evasion response by misregulating CD47. To understand how these
mechanisms of regulation are altered in cancer versus healthy cells, the proposed experiments will be carried
out mainly in patient-derived solid tumors (specifically breast cancer) and leukemia samples; and the results
will be compared with results from healthy donor samples. For this proposal, the following specific aims will be
performed: 1) Determine whether unique CD47 super-enhancers (SEs) are formed to respond to
inflammatory signaling to misactivate the immune evasion program in hormone-positive breast cancers.
2) Investigate whether CD47 enhancers or SEs are erroneously recruiting inputs (transcription factors)
that typically drive hematopoiesis develo...

## Key facts

- **NIH application ID:** 10242142
- **Project number:** 5K22CA226365-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Paola A Betancur
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $199,098
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242142

## Citation

> US National Institutes of Health, RePORTER application 10242142, Identification of Novel Gene Regulatory Interactions Driving the Immune Evasion Program Through Transcriptional Activation of CD47 in Cancer (5K22CA226365-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242142. Licensed CC0.

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