# KY INBRE Admin Supplement: The Role of Platinum Leaving Ligands in Chemo-immunotherapeutic Resistance in Lung Cancer Models

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2021 · $148,800

## Abstract

Project Summary/Abstract
Platinum chemotherapeutics are the primary treatment for nonsmall cell lung cancer (NSCLC), but due to the
prevalence of resistance to these compounds, the addition of PD-1 immunotherapy has become the standard of
care. However, chemotherapy has been shown to impact anti-tumor immunity by inducing PD-1 expression,
CD8+ T cell priming, and infiltration leading to immunogenic cell death. There is an urgent need to understand
the molecular mechanisms by which platinum-based chemotherapeutics impact the immune response in
NSCLC. To analyze the paradoxical effects of platinum compounds on the immune system, a systemically
designed and novel bank of platinum compounds with structural similarities to FDA-approved chemotherapeutic
will be used. Aim 1) In cellular models of lung cancer, the cell surface expression patterns of T Cell activators
will be examined. Both matrix metalloproteases and class I major histocompatibility complex, which play a role
in metal sensitivity, will be analyzed before and after exposure to the platinum compounds. We hypothesize that
leaving ligand differences of platinum compounds will impact the levels of these factors on the cell surface,
correlating to the cell-type-specific variances in platinum toxicity. Aim 2) The impact of the novel platinum
compounds on the adenosine dependent pathway through the production of tumor-derived prostaglandin E2
(PGE2) and modulation of the cell surface expression of CD73 will be determined. Our hypothesis is that
production of adenosine is stimulated by the indirect effects of chemotherapy on M-MDSCs via the following
steps: (a) chemotherapy induces PGE2 production in tumor cells; (b) the released PGE2 upregulates CD73 ecto-
5-nucleotidase enzyme on the surface of M-MDSCs; (c) CD73 catalyzes the production of adenosine from AMP
(derived from ATP released by dying cells); and (d) adenosine inhibits the activation of effector CD8+ T cells
within the tumors. The long-term goal of this proposal is to understand the mechanisms that mediate platinum
resistance and toxicity in NSCLC, ultimately leading to strategies to block any immunosuppressive effects of
chemotherapy. The study is innovative in both the signaling model proposed for the blockade of the immune
system and in the design of the platinum compounds that vary only at the leaving ligand.

## Key facts

- **NIH application ID:** 10399834
- **Project number:** 3P20GM103436-21S2
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** MARTHA E BICKFORD
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $148,800
- **Award type:** 3
- **Project period:** 2021-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399834

## Citation

> US National Institutes of Health, RePORTER application 10399834, KY INBRE Admin Supplement: The Role of Platinum Leaving Ligands in Chemo-immunotherapeutic Resistance in Lung Cancer Models (3P20GM103436-21S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399834. Licensed CC0.

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