Career Development Award
Diane Tseng, MD, PhD
University of Washington and Fred Hutchinson Cancer Center
Seattle
WA
Checkpoint immunotherapy has advanced treatment of NSCLC, but the majority of patients do not experience long-term disease control and are at risk for autoimmune-related side effects. In this study, Dr. Tseng will examine specialized cells called CD8+ T that express receptors (KIR+) that suppress autoimmunity to understand how these cells regulate the immune system’s cancer-fighting ability during checkpoint immunotherapy treatment. Insights gained from this study could result in better strategies for improving efficacy while decreasing immune-related side effects.
Research Summary
Checkpoint immunotherapy has greatly advanced the treatment of non-small cell lung cancer, but only a minority of patients experience long-term disease control and all patients are at risk for side effects related to inflammation in normal organs (known as autoimmunity). Notably, patients developing mild autoimmune side effects are reported to have improved response rates to checkpoint immunotherapy compared to patients that do not develop side effects. However, the scientific basis of this relationship between treatment efficacy and toxicity is not well understood. There has been a recent scientific breakthrough shedding light on a novel role of an immune cell subset involved in controlling autoimmunity. These specialized immune cells are CD8 T cells that express killer cell immunoglobulin-like receptors (KIR+ CD8+ T cells) and function to eliminate other immune cells that drive autoimmune disease. This study is examining the idea that KIR+ CD8+ T cells play an important role in controlling autoimmune side effects from checkpoint immunotherapy, but may also impact how well the immune system fights the cancer. The first goal of this study is to understand how the normal functions of KIR+ CD8+ T cells break down when patients develop autoimmune side effects from checkpoint immunotherapy. The second goal of this study is to understand the extent to which KIR+ CD8+ T cells regulates the immune system’s cancer-fighting capabilities. Better understanding the relationship between desirable immune responses against tumor and undesirable autoimmune toxicities can lead to better strategies for improving the effectiveness of immunotherapy and minimizing side effects.
Technical Abstract
Checkpoint immunotherapy has advanced the treatment paradigm for non-small cell lung cancer (NSCLC), but only some patients respond to treatment and many patients experience immune related adverse events (irAE). Understanding the distinct and overlapping mechanisms regulating anti-tumor immunity and autoimmunity due to checkpoint immunotherapy is critical for developing more effective and less toxic therapies. A subset of CD8+ T cells expressing killer cell immunoglobulin-like receptors (KIR) have recently been shown to suppress autoimmunity without impairing anti-viral immunity by eliminating autoreactive T cells. We reason that KIR+ CD8+ T cells may also play an important role in regulating autoimmunity arising from checkpoint immunotherapy. Furthermore, we reason that KIR+ CD8+ T cells may also regulate the activity of tumor-reactive T cells to varying degrees, since tumor-reactive T cells are a specialized type of autoreactive T cells. This study examines the hypothesis that KIR+ CD8+ T cells dampen autoimmunity and anti-tumor immunity during checkpoint immunotherapy treatment. To test this hypothesis, we will first interrogate the activity of KIR+ CD8+ T cells during the development of irAE after immune checkpoint blockade (specific aim 1). Next, we will evaluate the impact of KIR+ CD8+ T cells on anti-tumor immunity in NSCLC (specific aim 2). This study may shed light on the biological mechanisms regulating autoimmunity and anti-tumor immunity in lung cancer patients undergoing checkpoint immunotherapy. Insights gained from this study may pave the way toward clinical strategies for improving immunotherapy efficacy while minimizing irAEs.