# Monocyte promotion of therapy resistance by immune and non-immune mechanisms

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

## Abstract

Abstract
Immunotherapies such as checkpoint inhibitors have demonstrated exciting clinical responses in the recent
years, demonstrating the important role of host immune system in cancer. We were the first group to report a
novel population of immunosuppressive monocytes, characterized by a loss of HLA-DR expression
(CD14+HLA-DRlow/neg), in lymphoma, renal cell carcinoma, glioblastoma multiforme and other cancer types.
These cells are PD-1 positive in lymphoma tumors. We have characterized the suppressive functions of these
cells on systemic immunity and demonstrated correlation of these cells to decreased PFS and OS. Other
researchers have reported corroborative findings in other cancer types. While many in the field have termed
these cells as monocytic myeloid derived suppressor cells (MDSC) based on their immune functions, we have
also identified immune independent mechanism by which these cells directly promote chemo-resistance in
lymphoma. Therefore we believe that these cells have a broader spectrum of functions than MDSC and have
defined them as regulatory monocytes, Mreg. Our central hypothesis is that lymphoma tumor and Mreg
croos talk is a key mechanism that leads to suppression of anti-lymphoma immunity and
chemotherapy resistance, thereby, reducing survival. In this R01 proposal, we will examine Mreg
lymphoma crosstalk that promotes treatment resistance and identify potential therapeutic strategies. This will
be achieved through three specific aims: 1) Identify the mechanisms of Mreg mediated lymphoma
resistance to chemotherapy, specifically focusing on Hsp27 signaling. Animal model will be developed to
examine Mreg lymphoma interaction in chemo-resistance, including primary patient tumor xenografts and
testing of Apatorsen, an anti-sense oligonucleotide that inhibits Hsp27 in clinical trial development for solid
tumors. 2) Examine strategies to reprogram Mreg to improve anti-lymphoma immunity, specifically
testing blockade of Hsp27 and PD-1/PD-L1/L2 in lymphoma Mreg crosstalk and stimulation with toll-like
receptor-7 (TLR7) agonist. In addition we will examine a novel liposome-packaged drug delivery system to
target Mreg. 3) Identify the prognostic significance of intra-tumor Mreg. Completion of Aims 1 and 2 will
identify more than one potential treatment strategies targeting Mreg lymphoma crosstalk for clinical trial
development. Completion of Aim 3 will assist the development of a personalized therapy approach where
patients with high levels intra-tumor Mreg will receive therapy targeting Mreg lymphoma crosstalk.

## Key facts

- **NIH application ID:** 9983617
- **Project number:** 5R01CA203836-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Yi Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $363,713
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983617

## Citation

> US National Institutes of Health, RePORTER application 9983617, Monocyte promotion of therapy resistance by immune and non-immune mechanisms (5R01CA203836-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983617. Licensed CC0.

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