Combinatorial application of nanoscale technologies to target a novel mechanism of immune evasion by cancer cells

PROJECT SUMMARY Immunotherapy holds the promise of a cure for cancer. However, only a subset (<20%) of patients exhibit durable response to immunotherapy. This is because immune checkpoint inhibitors need immune cells in the tumor. However, many tumors are found to be immunologically barren or cold, i.e. lack tumor infiltrating lymphocytes (TILs). Overcoming this barrier is key to a cure for cancer. We recently discovered that cancer cells form physical nanoscale tentacles (tunneling nanotubes) to connect with and harvest mitochondria from immune cells, which depletes the immune cells. Recent evidence show mitochondria-harvesting tumors have poor clinical outcomes. There is is an unmet need to target this novel mechanism of immune evasion. There are two distinct and complementary strategies to achieve this goal: (1) Engineer CAR-Ts or TILS with extra mitochondria (augmented T cells) such that any loss of mitochondria to cancer cells doesn’t not fully deplete the immune cells of their metabolic capacity; and (2) Disable the ability of a cancer cell to form nanotubes to harvest immune cell mitochondria. In this proposal, we aim to develop an immunotherapeutic regimen that combines these two strategies with an immune checkpoint inhibition. Specifically, We will evaluate different organelle transplantation technologies for delivering mitochondria, a nanoscale structure, to a T cell ex vivo prior to infusion as cell therapy (Aim 1); (2) Test the antitumor efficacy of these mitochondria-augmented T cells in combination with a drug that inhibits the capability of cancer cells to form nanotubes and an immune checkpoint inhibitor (Aim 2); and Dissect the mechanisms underlying mitochondrial harvesting (Aim 3). These studies can lead to paradigm shift in immunotherapy and generate fundamental insights into cancer-immune cell communications at the nanoscale.