2021 LCRF-AstraZeneca Research Grant
Lingtao Jin, PhD
University of Texas Health Science at San Antonio
Research Project:
Targeting tumor-immune microenvironment to improve durvalumab efficacy in small cell lung cancer
Summary:
Small cell lung cancer that accounts for around 15% of lung cancer cases is the most aggressive subtype of lung cancer with a five-year survival rate of less than 5%. The results of numerous clinical trials have been disappointing and, and as a result, treatment options for small cell lung cancer have not had the same progress as non-small cell lung cancer. Anti-PD-L1 immunotherapy such as durvalumab has recently received FDA approval as a first line therapy for small cell lung cancer. This approval is an important advance for patients with small cell lung cancer, whose treatment strategies and clinical outcomes had remained unchanged for more than three decades. Compared with chemotherapy alone, however, adding anti-PD-L1 therapy only moderately extends patient survival. Such modest efficacy of immunotherapy in small cell lung cancer highlights the unmet need for more effective combination therapy approaches.
To investigate how anti-tumor immunity is suppressed in small cell lung cancer, Dr. Jin’s lab explored that tumor-derived exosomes, a small vehicle released by cancer cells that contain lipids, proteins, sugars, etc, may play a critical role in suppressing anti-tumor immunity. Further analysis revealed that these tumor-derived exosomes contain a large quantity of lipids, which can compromise the function of dendritic cells, a type of immune cells that play a key role in facilitating anti-tumor immunity. Therefore, Dr. Jin’s lab will further evaluate whether blocking tumor-derived exosome-induced dendritic cell suppression could be used to boost anti-tumor immunity and improve the efficacy of durvalumab in small cell lung cancer.
Final report:
The first aim was to identify key long chain fatty acids from tumor-derived exosomes that result in dendritic cell dysfunction in small cell lung cancer (SCLC). The researcher identified C16:0 as a fatty acid that directly suppressed the T-cell priming of dendritic cells in the tumor microenvironment. C160 induced PPARα expression. By using an inhibitor of PPARα, the effect of C160 was blunted indicating the important role it plays in dendritic cell dysfunction. Arginase I, an immune suppressive enzyme exploited by macrophages and myeloid-suppressor cells, is a downstream effector that induces dendritic cell dysfunction. As part of aim 2 the researcher treated SCLC animal tumor models with a combination of immunotherapy (PD-L1 antibody) and the PPARα inhibitor GW6471. This combination led to regression of SCLC established tumors and significant improvement of survival compared with mono-therapies.
Impact:
SCLC is a very difficult cancer to treat. The biggest advance in recent years has been treatment with the addition of immunotherapy to chemotherapy. This has resulted in an improvement in survival for patients, but the benefit has been modest at best. New treatment strategies are still an area of great need. The immune system is very complex and there is a great deal of research going on to develop treatments to augment the effect on the immune system. This researcher is studying the tumor microenvironment to identify potential targets for treatment. Preliminary data suggest that an inhibitor of PPARα can augment the effect of immunotherapy in mouse models of SCLC. Although the work is still at an early stage, this represents an effort to identify novel targets for treatment. This has the potential to eventually lead to a clinical trial in humans.