Pilot study of circulating immune checkpoint proteins in persons with and without cancer
Principal Investigator
Name
Kara Michels
Degrees
PhD, MPH
Institution
Albert Einstein College of Medicine
Position Title
Assistant Professor
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
2026-9129
Initial CDAS Request Approval
Mar 26, 2026
Title
Pilot study of circulating immune checkpoint proteins in persons with and without cancer
Summary
Our immune system can kill damaged epithelial cells, such as infected or cancerous cells. T lymphocytes and natural killer (NK) cells are key players in this process. However, tumors often express proteins that regulate the activity of immune cells. These immune checkpoint proteins (ICPs) send signals that turn the cytotoxic functioning in immune cells on or off, sometimes permanently (exhaustion)—conferring a survival advantage for cancer cells via immune evasion. Expression of ICPs is considered a hallmark of cancer. As such, these proteins are often studied in the context of tumor expression or as immunotherapeutic targets. Most research has focused on cytotoxic T lymphocyte associated protein 4 (CTLA-4) and the B7 family of proteins, particularly programmed death-ligand 1 (PD-L1/B7-H1). Many other proteins are gaining scientific interest as ICPs because they similarly alter T and NK cell functioning.
Importantly, tissue expression of ICPs is associated not only with cancer, but also cancer-related risk factors such as infectious exposures, obesity, and sex steroid hormones. Additionally, ICPs can be measured in circulation; studies show circulating ICPs can be detected in persons with and without cancer. Taken together, this suggests ICP expression may begin before clinically recognizable tumor formation. It may be possible that circulating levels of these proteins change over time either due to oncogenesis, or to risk factor exposures that have the potential to prime tissues for tumor formation. We hypothesize that cancer-associated changes in circulating ICP concentrations can be measured years before a cancer diagnosis typically occurs.
Existing studies examining circulating ICPs have measured only one or two proteins at a time, are cross-sectional, and results across these studies are inconsistent. We identified only one prospective study on any of the ICPs that are of interest in our research; this study used an untargeted, relative-quantification-based platform to report reduced colorectal cancer risk in men with lower circulating MICA levels.
Ultimately, in a future grant, we want to create a case-cohort study in PLCO to determine if circulating levels of 12 ICPs can be used to estimate future cancer risk, for multiple cancer types. These ICPs are implicated in the regulation of CD8+ T cell and NK cell activity, are expressed in a range of tumor tissues, and/or have been detected in circulation. Eventually, our innovative research will challenge assumptions about the utility of measuring ICPs prospectively, but given the sparsity of research on circulating ICPs, we first need to establish that each of our novel ICPs is a biomarker of existing cancer, and that it can be measured in stored serum collected in red top tubes (i.e., the matrix collected by PLCO). Therefore, this pilot study is proposing to use a targeted multiplex assay to measure absolute concentrations of these 12 novel ICPs within 40 ul of serum collected from n=22 healthy donors and n=50 persons with cancer in PLCO.
Aims
1.To quantify mean concentrations of 12 ICPs within stored red top serum tubes collected from persons with and without cancer (defined as primary invasive lung, colorectal, ovarian, endometrial, or gastric adenocarcinomas). In this aim, we will develop an understanding of the potential differences in means that might be detectable between these groups in a larger study. This objective will inform power calculations for our grant and shed light on whether concentrations of a given protein can be expected to be high or low in persons with cancer. The rationale for these cancer types will be described in our full application.
2. To determine if mean concentrations of the ICPs may differ between cancer types, based on organ site. This aim will help us understand if all of the ICPs, or perhaps a parsimonious set of ICPs, could be studied for multi-cancer detection in the larger grant.
3. To characterize differences in ICP concentrations between people with low and high grade cancers. These results will explore whether there may be “dose-response” relationships between tumor grade and circulating ICP levels, and will help us determine if the grant should focus on only high grade cancers as outcomes. Analyses will be conducted for all cancer types together, and by organ site.
Collaborators
Kara Michels (Albert Einstein College of Medicine)
Peter Campbell (Albert Einstein College of Medicine)