# The role of nuclear PD-L1 in breast tumor cell division, progression and therapy response

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $363,713

## Abstract

Triple negative breast cancer (TNBC) [estrogen receptor (ER), progesterone receptor (PR), and human
epidermal growth factor receptor 2 (HER2) negative breast cancer is an aggressive subtype of breast cancer
for which there are no approved targeted therapies. While standard chemotherapy reduces the risk of a
disease event, patients with residual TNBC after neoadjuvant chemotherapy have a high risk of locoregional
recurrence despite surgical resection and aggressive postoperative radiotherapy. Therefore, better
understanding mechanisms of TNBC progression and identifying novel treatment approaches for
patients who have progressed on standard treatment are of great needs. PD-L1 is overexpressed in
TNBC, relative to normal breast tissue and other breast cancer subtypes. Aberrant PD-L1 expression on
tumors is an important means of evading elimination by its host immune system. The binding of programmed
death ligand 1 (PD-L1) to its receptor, programmed cell death protein 1 (PD-1) transmits signals that inhibit T-
cell activation. Therefore, abrogating the PD-1/PD-L1 interaction with therapeutic antibodies has been explored
as a means to enhance antitumor immunity. Although the extracellular role of PD-L1 in the regulation of T-cell
responses has been well studied, potential intracellular functions of PD-L1 in cancer remain largely
unknown. Surprisingly, we have found that TNBC proliferation requires PD-L1 and a subset of PD-L1 localizes
in the nucleus and interacts with cohesin, a protein complex that is important for appropriate chromosome
alignment and segregation during the cell cycle. Our Preliminary Data suggest that PD-L1 directly regulates
cohesion function in TNBC. Knocking down PD-L1 dramatically causes incomplete chromosome segregation
and inhibits TNBC cell proliferation, while has no effect on normal cells. The central hypothesis being tested
in this proposal is that PD-L1 regulates cell cycle and chromosomal stability in triple negative breast
cancer (TNBC), and targeting the intracellular/nuclear function of PD-L1 or pathways (mitosis and
cohesin) regulated by PD-L1 is of therapeutic use. We propose to test this central hypothesis in the
following Specific Aims: Aim 1, Determine the role of PD-L1 in regulation of cell cycle, genomic stability, and
tumor cell proliferation by studying the exact mechanisms by which nuclear PD-L1 might regulate cohesion.
Aim 2, Study the regulation of PD-L1 during cell cycle and mitosis. Aim 3, Evaluate the inhibition of PD-L1
nuclear function on chromosome segregation, tumor growth and response to radiochemotherapy both in vitro
and in animal models. The overall impact from the successful completion of this work will be a more complete
understanding of the role of PD-L1 in cancer pathogenesis. In addition, our work will lead to the design of more
rational and effective combination therapies for TNBC patients by defining novel strategies that not only
enhance cancer therapy by inhibiting mitosis but also un...

## Key facts

- **NIH application ID:** 9897018
- **Project number:** 1R01CA239164-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Zhenkun Lou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,713
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897018

## Citation

> US National Institutes of Health, RePORTER application 9897018, The role of nuclear PD-L1 in breast tumor cell division, progression and therapy response (1R01CA239164-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897018. Licensed CC0.

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