# Regulatory Dendritic Cells in Cancer

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $367,650

## Abstract

The long term of these studies is to understand and target the immunosuppressive activity of
leukocytes with phenotypic attributes of inflammatory dendritic cells (DCs) that accumulate at
tumor beds. This proposal focuses on elucidating and targeting the mechanisms of inhibition of
αβ T cells by members of the butyrophilin family overexpressed in regulatory DCs and
macrophages in ovarian cancer. Key findings for the ongoing grant have been: 1) The
demonstration that novel antibodies targeting BTN3A1/2/1 rescue αβ T cells from butyrophilin-
mediated suppression; 2) the identification of members of the TCR complex and receptor
phosphatases that co-IP with BTN3A1; and 3) the finding that BTN3A1/2/3 are universally
overexpressed in inflammatory DCs and other myeloid cells in ovarian cancer. Based on these
and other findings, our central hypothesis is that BTN3A1 inhibits tumor-reactive T cells by
engaging a multimeric CD45 phosphatase:CD3:TCR complex, which antagonizes
phosphorylation-dependent TCR signal transduction by increasing the density of CD45 at the
TCR network. In contrast, antibody-induced conformational changes in BTN3A1 elicit the
activation of Vγ9Vδ2 T cells. Accordingly, our Specific Aims are:
In Specific Aim 1, we will determine the anti-tumor effectiveness of targeting human
BTN3A1 in vivo in tumor-bearing hosts.
 In Specific Aim 2, we will elucidate the molecular mechanism of T cell inhibition
mediated by BTN3A1, based on the identification of a multimeric complex that co-IPs with
BTN3A1.
 In Specific Aim 3, define the mechanism of BTN3A1 deregulation at tumor beds.
 Our work could exert a profound effect in the field by elucidating a novel targetable immune
checkpoint inhibitory pathway mediated by butyrophilins universally overexpressed in ovarian
cancer. This mechanistic rationale will pave the way for a novel generation of immunotherapies
that could benefit patients currently resistant to established immune checkpoint inhibitors, which
may be applicable other lethal tumors and could be relevant for other “orphan” B7 ligands.

## Key facts

- **NIH application ID:** 9858276
- **Project number:** 5R01CA124515-15
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Jose R Conejo-Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,650
- **Award type:** 5
- **Project period:** 2007-07-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858276

## Citation

> US National Institutes of Health, RePORTER application 9858276, Regulatory Dendritic Cells in Cancer (5R01CA124515-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858276. Licensed CC0.

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