# Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $364,593

## Abstract

PROJECT SUMMARY
Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a five-year survival rate of less
than 5%. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1/PD-L1 antibodies has demonstrated
unprecedented clinical activity in several difficult-to-treat cancers, with durable responses in a subset of patients.
Anti-PD-L1 antibodies such as atezolizumab, for example, have been recently received FDA approval as first
line treatment in combination with platinum-based chemotherapy for SCLC; however, the efficacy seems modest.
The mechanistic basis for the modest efficacy of immune checkpoint inhibitor in SCLC remains unknown but
mounting evidence suggests that the immunosuppressive nature of tumor microenvironment dictates the poor
efficacy of immunotherapy in SCLC. In addition, the potential impact of platinum-based chemotherapy on anti-
tumor immune response may also play an important role in determining the efficacy of immunotherapy.
 Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses.
Emerging evidence indicates that the tumor microenvironment induces immune dysfunctional tumor-infiltrating
DC (TIDC), characterized with both increased intracellular lipid content and mitochondrial respiration. The
underlying mechanism, however, remains largely unclear. Here, we found that fatty acids-carrying tumor derived
exosomes (TDEs) induce immune dysfunctional DC to promote immune evasion. We also discover that platinum,
the front-line treatment for SCLC, further exacerbates TDE-induced DC dysfunction through reprograming of
glutamine-lipid metabolism in SCLC. Mechanistically, platinum rewires glutamine metabolism to promote fatty
acid synthesis, leading to enrichment of long chain fatty acids in TDEs. As a result, TIDCs uptake TDEs with
large amount of fatty acids that activates peroxisome proliferator activated receptor  (PPAR) signaling, leading
to aberrant lipid accumulation and elevated FAO activity, which culminates in the induction of
immunosuppressive enzyme arginase 1 (Arg1) and consequently dysfunction in TIDCs. Genetic depletion or
pharmacologic inhibition of PPAR effectively attenuates TDE-induced DC-based immune dysfunction and
enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in
DCs and reveals that PPARlies at the center of metabolic-immune regulation of DCs, suggesting a potential
immunotherapeutic target. As such, targeting PPAR can be exploited to improve anti-cancer immunotherapy.
We will test our hypothesis through the following aims: Aim 1: To explore how TDEs activate PPAR and induce
Arg1 to drive DC dysfunction. Aim 2: To investigate how platinum rewires glutamine metabolism in SCLC to
induce dendritic cell dysfunction and immune evasion. Aim 3: To evaluate the efficacy of Chemo/anti-PD-
L1/PPAR inhibitor combination in SCLC.

## Key facts

- **NIH application ID:** 10419937
- **Project number:** 1R01CA269782-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Lingtao Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,593
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419937

## Citation

> US National Institutes of Health, RePORTER application 10419937, Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC (1R01CA269782-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10419937. Licensed CC0.

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