Summary The therapeutic targeting of cancer cells’ ability to evade immune surveillance has revolutionized the treatment of many cancers. Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAb) reactivate cancer patients’ (pts’) immune systems to attack tumor cells thus eliciting response even in advanced disease. Unfortunately, durable response rates remain relatively low (~25%), and it is currently unclear what limits ICI response. Retrospective analyses of clinical pharmacology data reveal a strong correlation between elevated ICI clearance (CL) and reduced ICI response that is also associated with cancer cachexia, though independent of circulating ICI levels or ICI target receptor occupancy. Suppressive immune populations are elevated in pts with non-small cell lung cancer (NSCLC) and in multiple animal models of cachexia, but how these immune populations differ in numbers or function in cachectic vs. non-cachectic pts is poorly understood. The neonatal Fc receptor, FcRn (FCGRT), is a key mediator of IgG and albumin homeostasis with dual roles in recycling (i.e. slowing the CL of) both IgG and albumin in immune cells. Project Hypothesis: FcRn modulation in myeloid populations, triggered by yet unidentified cachexia-associated signaling, leads to elevated CL and poor ICI response. Preliminary data: 1) murine models replicate increased pembro CL in tumor-bearing cachectic mice relative to non-cachectic tumor-bearing mice and tumor-free controls; 2) increased CL of other mAbs, including anti-murine PD-1 mAb RMP1-14 in cachectic mice relative to non-cachectic mice; 3) decreased Fcgrt in liver of cachectic vs. non-cachectic mice; 4) immunosuppressive immune cell populations are elevated in pts with NSCLC and correlate with poor ICI responses; 5) increased myeloid and dendritic cell populations in pts and in mice with cancer-induced cachexia; and 6) paradoxical apparent elevation of FcRn protein in these immune cell populations in pts and mice. Project Objective: To identify mechanisms linking cachexia, elevated ICI mAb CL and poor response to ICI therapy. Specific Aims: Aim 1. To identify tissues with elevated mAb CL, altered FcRn and macrophages in cachectic mice. We expect to identify tissues/organs, immune cell populations, and FcRn expression/functional differences responsible for elevated CL in cachectic vs. non- cachectic mice. Aim 2. To determine whether cachexia affects myeloid-derived immune cells leading to poor ICI efficacy. We expect cachexia will alter myeloid-derived immune populations and FcRn function resulting in poor ICI mAb anti-tumor responses. Aim 3. To determine how cachexia affects anti-tumor immunity and pembro CL in NSCLC pts. We expect myeloid immune populations from cachectic pts will display modulated FcRn expression and function that drives decreased efficacy and elevated CL of anti-PD-1 treatment. Impact: Despite the remarkable promise of ICI therapies, durable responses remain rare, and causes of resistance unclear. Our project interrogates probable mechanisms linking poor clinical outcomes to ICI clearance and cachexia in NSCLC, which may reveal improved strategies for broadly overcoming ICI resistance.

Narrative The proposed research is relevant to public health because an improved understanding of which cancer patients are most likely to benefit from immune checkpoint inhibitor therapy and why some patients do not respond to treatment will lead to meaningful improvements in therapy selection and new strategies for overcoming therapeutic resistance. Research shows a clear link between elevated immune checkpoint inhibitor clearance and poor response that is decoupled from circulating levels of therapeutic in some patients. A better mechanistic understanding of patient factors governing elevated immune checkpoint inhibitor clearance could have a major impact on cancer related mortality by improving utilization of immune checkpoint inhibitor therapy.