# Novel mechanism of chemokine nitration in bladder cancer

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $389,848

## Abstract

PROJECT SUMMARY
The recent approval of immunotherapies has revolutionized the approach to managing bladder cancer (BCa).
Nevertheless, complete response is observed in only a minority of patients and there are no unambiguous
biomarkers to guide treatment selection. A key factor that controls tumor growth and response to cancer immune
therapy is the recruitment of immune cells to the tumor microenvironment by chemokines.
The chemokine CCL2 (C-C motif ligand 2) is best known for its ability to induce the trafficking of immune cells
by binding its primary receptor, CCR2. The recruitment of immunosuppressive myeloid cells by CCL2 promotes
cancer in several tumor types. In the bladder, however, we show an unexpected finding that CCL2 and its
receptor CCR2 are protective against cancer development and growth and the mechanism is T cell-dependent.
We also show that post-translational nitration of CCL2 by bladder tumors inhibits CCL2’s ability to recruit T cells
and its effects on tumor control. This may be one of the critical reasons behind the failure of chemokines in
clinical trials and may explain certain paradoxes that are seen between CCL2 levels and patient outcomes in
cancer. We propose delineating the effect of CCL2 nitration on the biology of BCa by using nitration-resistant
recombinant CCL2 (rCCL2NR) which may restore bladder tumor T cell recruitment and facilitate anti-tumor T cell
immunity.
Based on convincing preliminary data, we hypothesize that nitration of CCL2 in BCa ablates the tumor protective
function of CCL2/CCR2 by disrupting T cell recruitment to bladder tumors. To address this hypothesis, two
specific aims are proposed. In Aim 1, we test the hypothesis that blocking nitration of CCL2 by rCCL2NR reduces
BCa progression by enhancing the recruitment of CCR2+ T cells in the bladder. rCCL2NR treatment effects will
be tested by intravesically instilling rCCL2NR vs rCCL2 vs control PBS weekly in the bladder. We will also
delineate the specific mechanisms by which rCCL2NR exerts its tumor-protective effect and test whether rCCL2NR
increases CCR2+ T cell recruitment or increase the activation and cytotoxicity of already recruited CCR2+ T cells
in the bladder. rCCL2NR will be evaluated either as a single agent or in combination with standard BCa treatment
strategies. Aim 2 will test whether nitrated CCL2 level in human bladder tumors is a prognostic factor and
predicts treatment response to immune therapy in BCa patients. Multiplex immunofluorescence will be used to
detect unmodified and nitrated CCL2 levels in BCa tissue microarray. We will also test whether intravesical
human rCCL2NR treatment results in increased recruitment of T cells in a humanized murine model of BCa. The
focus of this proposal is to develop an in-depth understanding of a novel cellular trafficking mechanism of immune
cells in the biology of BCa and the development of a breakthrough immunotherapy strategy that will potentially
improve the landscape of BCa treatment. ...

## Key facts

- **NIH application ID:** 10878517
- **Project number:** 1R01CA281726-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Neelam Mukherjee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,848
- **Award type:** 1
- **Project period:** 2024-05-03 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878517

## Citation

> US National Institutes of Health, RePORTER application 10878517, Novel mechanism of chemokine nitration in bladder cancer (1R01CA281726-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878517. Licensed CC0.

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