Immunometabolic T cell profiling as a prognostic liquid biopsy in NSCLC

Lung cancer is the leading cause of cancer death and accounts for more than 160,000 deaths each year. Immunotherapy, aimed at improving the immune system’s response to cancer, has recently emerged as a profound breakthrough for patients with lung cancer. In particular, therapies targeting the programmed death-1 (PD-1) pathway have been successful. PD-1 is a molecule on immune cells, called T cells, that serves as the “brakes” of the immune system, and tumors can exploit this pathway to shut down the potentially effective anti-tumor immune response. PD-1 immunotherapy blocks this cancer-enabling pathway and allows the immune system to reject tumors. Recently, the FDA has approved PD-1 blockade in combination with traditional chemotherapy for the treatment of metastatic non-small cell lung cancer (NSCLC). This combination approach has resulted in significantly longer survival compared to chemotherapy alone. Despite this, many patients still do not achieve clinical benefit or extended survival. Prior studies have shown that tumors with a high number of genetic changes, called “mutations”, respond favorably to PD-1 immunotherapy, possibly because these mutations induce more immune activation that can then be unleashed following blockade of the PD-1 pathway. However, we are unsure how mutations play a role in the response to PD-1 blockade in combination with chemotherapy which, counter to PD-1 blockade, has traditionally been thought to dampen the immune system. It is therefore of immediate urgency that we understand how PD-1 blockade and chemotherapy work together to promote tumor regression and longer survival and to help clinicians better select patients most likely to benefit from these treatments. Here we propose to evaluate the effect of treatment on anti-tumor immune responses in patients receiving anti-PD-1 in combination with chemotherapy versus those receiving anti-PD-1 alone. The findings from this study will significantly advance our knowledge of the immune response to lung cancer and may result in a paradigm shift in how we select patients who are most likely to benefit from PD-1 immunotherapy.