# Ongoing inflammation following chemotherapy induces immunosuppression

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2020 · $273,000

## Abstract

Conventional chemotherapy has been thought to act through the direct killing of tumor cells. However,
accumulating evidence indicates that immune competence is crucially required for chemotherapy efficacy. It is
expected that loss of this immunity during chemotherapy has a negative effect on its efficacy. Therefore, the
impact of chemotherapy on anti-tumor immunity needs further investigation in order to rationally design
combinatorial regimens for conventional chemotherapy. In the preliminary studies, we have demonstrated that
repeated chemodrug gemcitabine (GEM) treatment promoted the expansion and differentiation of
immunosuppressive Ly6Chigh monocytic-MDSC (M-MDSC). Tumor-derived soluble factors, such as GM-CSF and
soluble ICAM-1(sICAM-1), were up-regulated upon chemo-drug treatment. In tumor-free naïve mice, GEM
treatment induced the immunosuppressive activity of Ly6Chigh myeloid cells in the bone marrow (BM). The
chemokine CX3CL1 and its receptor CX3CR1 expression levels were elevated in the BM. Higher levels of
mitochondrial reactive oxygen species (mtROS) were also observed in tumor cells and BM stromal cells following
chemotherapy. Furthermore, chemotherapy induced NF-κB activation leading to the hyperproduction of GM-CSF
by tumor cells. Based on these preliminary data, we hypothesize that chemotherapy enhances the production of
mtROS in tumor cells and BM stromal cells, which increases the expressions of GM-CSF and sICAM-1 as well
as CX3CL1 leading to the enhanced immunosuppression of M-MDSC in the TME. These hypotheses will be
addressed by two Specific Aims. Aim 1 defines the roles of GM-CSF and sICAM-1 in chemotherapy-induced
differentiation of immunosuppressive Ly6Chigh myeloid cells and the mechanisms underlying mtROS and
upregulation of GM-CSF and sICAM-1 in tumor cells; Aim 2 determines the mechanisms by which host cell-
derived chemokine CX3CL1 regulates the accumulation and immunosuppressive function of inflammatory
Ly6Chigh myeloid cells in the BM. The findings from these studies will allow us to gain a better understanding the
underlying mechanisms by which ongoing inflammation following multi-dose clinical regimens of chemotherapy
modulates anti-tumor immunity, and rationally design a novel therapeutic approach by combining chemotherapy
with mitochondria-targeted antioxidants for cancer treatment.

## Key facts

- **NIH application ID:** 9854339
- **Project number:** 1P20GM135004-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Chuanlin Ding
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $273,000
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854339

## Citation

> US National Institutes of Health, RePORTER application 9854339, Ongoing inflammation following chemotherapy induces immunosuppression (1P20GM135004-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9854339. Licensed CC0.

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