Shiladitya Sengupta, PhD

Lung cancer is a devastating disease. Despite the success of immune checkpoint inhibitors (ICIs), only a subset of patients respond to treatment. One of the main factors limiting the efficacy of ICIs is that tumors often do not have immune cells. In a recent study, published in Nature Nanotechnology (2022), we demonstrated that cancer cells harvest immune cell mitochondria (small organelles responsible for energy generation and cellular signaling) by forming tiny intercellular tunneling tubes called nanotubes. We found that the immune cells that lost mitochondria died, contributing to the loss of immune cells in the tumor, and rendering ICIs ineffective. In this research project, we will explore, for the first time, this novel mechanism of immune evasion in an array of lung cancers (with diverse genetic background), and test a novel class of inhibitors that target a central driver of nanotube formation. These inhibitors can emerge as a new class of immunotherapies that address the loss of immune cells in tumors. The combining these with ICIs can be a paradigm shift in the treatment of lung cancer.

Update:

In the first year, our goal was to confirm that lung cancer cells harvest immune cell mitochondria by forming tunneling nanotubes and understand the consequence of this mitochondrial loss. In year 2, our goal is to disrupt this process by targeting a protein complex called the exocyst complex. We have made significant progress, validating this phenomenon in lung cancer, and synthesizing a library of small molecules that can disrupt the process. We have also optimized methods to specifically deliver an immunotherapy agent to lung tumors. Our research can lead to fundamental insights into a novel mechanism of immune evasion by lung cancer, and potentially lead to a new generation of immunotherapy agents.

Supported by the Mary Fuller Russell Fund