Quantifiable TCR repertoire changes in pre-diagnostic blood specimens among high-grade ovarian cancer patients

The National Cancer Institute awarded the Children's Hospital of Philadelphia a $610,970 cooperative agreement on September 1, 2026, to develop and validate a T cell receptor (TCR)–based biomarker for prediagnostic detection of high-grade serous ovarian carcinomas (HGSOC) using blood specimens collected before clinical diagnosis.

The project addresses the clinical challenge that most HGSOC cases are diagnosed at advanced stage (Stage III or IV), when five-year survival is approximately 30 percent, whereas stage-specific survival exceeds 90 percent when caught at Stage I. Current screening modalities including serum CA-125, HE-4, and transvaginal ultrasound lack the sensitivity to detect early-stage lesions and have not reduced ovarian cancer mortality in large trials. The research leverages the fact that HGSOC frequently develops p53 mutations and DNA mismatch repair deficiencies during early progression, creating tumor-associated antigens that trigger adaptive immune responses and produce quantifiable TCR repertoire changes in circulating T lymphocytes years before conventional diagnosis.

The work is performed at the Children's Hospital of Philadelphia Research Institute in Philadelphia, Pennsylvania, with a period of performance from September 1, 2026, through August 31, 2031. The funding supports the Cancer Detection and Diagnosis Research program (CFDA 93.394), which funds screening, early detection, and diagnostic methods for cancer.

Abstract

High-grade serous ovarian carcinomas (hgsoc) comprise 70% of sporadic ovarian cancers (OC) and caused most OC-related deaths. Hgsocs are dominantly diagnosed at stage III or IV, with 5-year survival only 30%. If diagnosed at stage-i when tumors are locally confined, the disease is curable with over 90% 5-year survival. However, majority of hgsocs originated from microscopic tumor lesions called serous tubal intraepithelial carcinoma, or stic, in the fallopian tube, which subsequently spread to the ovaries and peritoneal cavity. This property of stic renders hgsocs to be metastatic at very early stage of tumor progression and only less than 10% hgsoc patients are diagnosed at stage-i. Existing biomarkers, or imaging scans, such as serum CA-125, he-4, transvaginal ultrasound, etc, suffer from low sensitivity to detect the small hgsoc lesions at early-stage. As a result, large screening trials have shown that these clinical modalities cannot reduce OC-related mortality. On the other hand, hgsocs frequently develop P53 mutations and deficiencies in DNA mismatch repair machinery during early progression. These events create tumor antigens that can trigger adaptive immune responses. As a critical component in the immune system, the t lymphocytes specifically target these antigens via their t cell receptors (TCR), followed by t cell activation and massive proliferation. Finding cancer-associated changes in the blood t cell repertoire thus provides a rational solution to the diagnosis of hgsocs in its early stage, which usually happens years before their conventional diagnosis. Here, we propose to develop and validate a TCR-based non-invasive biomarker for the prediagnostic detection of hgsocs. The search for cancer-related signals among t cells is challenging given the enormous diversity of the human TCR repertoire and limited knowledge of t cell antigen specificity. My team pioneered this direction by developing computational methods to study the TCR repertoire, including trust to assemble tcrs from cancer genomics datasets, ismart to group antigen-specific tcrs, deepcat to perform DE novo prediction of cancer-associated tcrs and giana for ultrafast TCR clustering and disease classification. To prepare for this task, we have collected TCR repertoire sequencing samples from patients with malignant or benign ovarian malignancies and nurses' health study participants with blood specimens collected up to 5 years before hgsoc diagnosis. This unique sample cohort allowed US to investigate the landscape of blood TCR repertoire in OC patients. Using a new TCR embedding method, we identified significantly altered repertoire components in hgsoc compared to benign patients. Importantly, these components captured a quantifiable TCR repertoire change up to 4 years before conventional hgsoc diagnosis. Motivated by this exciting result, we will leverage the plco patients with prediganostic samples collected within 6 years prior to cancer diagnosis (n=81) to develop a TCR-based biomarker through a new computational framework (aim 1) and perform independent validation using the plco samples (aim 2), with the goal of reaching a positive prediction value of 5% for early-stage hgsocs.