# Myeloid cell-derived Granzyme B as an inducible enhancer of cancer immunotherapy

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $352,513

## Abstract

PROJECT SUMMARY
 Our broad, long term objective is to understand the molecular details of Fcγ receptor (FcγR) function,
with the goal of improving monoclonal antibody therapy for cancer. The antitumor effects of antibody therapy
are largely mediated by FcγR, which become clustered and activated upon binding to the Fc portion of
antibodies. Monocytes and macrophages are essential for antibody therapy to be effective, and FcγR
activation in these cells can lead to pleiotropic responses. These include phagocytosis, antibody-dependent
cellular cytotoxicity (ADCC), production of inflammatory cytokines, or a combination of these. Amongst these
activities, the mechanisms by which monocytes / macrophages carry out ADCC remain the least understood.
 We have recently found that FcγR clustering can induce Granzyme B production by human monocytes and
that ligands for Toll-like receptors (TLR) 4 and 8 can significantly enhance this response, as well as induce
Granzyme B themselves. Granzyme B is a serine protease expressed predominantly by natural killer (NK) cells
and CD8+ T cells, and is required for their cytotoxic functions. Given the central role of Granzyme B in NK cell-
mediated ADCC, our finding that monocytes can also produce Granzyme B is remarkable as it provides an as-
yet undiscovered anti-tumor function of monoclonal antibodies. Most notably we have also found that nurse-
like cells (NLCs) generated from CLL patient blood also produce Granzyme B following FcγR activation and
TLR8 ligand treatment, and they can engage in Granzyme-dependent ADCC of CLL cells. This latter
observation is of particular interest, as NLCs typically promote CLL-cell survival and proliferation. We therefore
hypothesize that Granzyme B production by monocytes and NLCs represents a critical aspect of the effector
response to antibody-coated target cells. We propose to explore the significance of these findings specifically
related to CLL immunotherapy in the following 3 specific aims: 1) Elucidate the mechanisms of Granzyme B
induction by FcγR in monocytes/macrophages and NLCs, 2) Determine the mechanism of augmentation of
FcγR-induced Granzyme B production by immune modulators and 3) Analyze the expression and function of
Granzyme B by monocytes and monocyte-lineage cells in patient samples and mouse models of CLL.
 Upon completion of this study we will have fully explored an entirely new mechanism of antibody-mediated
destruction of tumors by monocytes/macrophages and NLCs. These mechanistic studies will significantly
enhance our understanding of ADCC mediated by these cells, and will likely provide information that can lead
to the further enhancement of antibody therapy.

## Key facts

- **NIH application ID:** 10132996
- **Project number:** 5R01CA203584-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jonathan P. Butchar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,513
- **Award type:** 5
- **Project period:** 2017-04-10 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132996

## Citation

> US National Institutes of Health, RePORTER application 10132996, Myeloid cell-derived Granzyme B as an inducible enhancer of cancer immunotherapy (5R01CA203584-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132996. Licensed CC0.

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