Biologic and immunologic characteristics of ovarian cancers that are associated with p53 autoantibodies.
Abstract
Autoantibodies (AAbs) against p53 develop in a fraction of patients with ovarian cancer, but the mechanisms underlying their development remain unknown. High-grade serous carcinoma (HGSC) is the most prevalent and lethal histotype, and nearly all HGSCs exhibit TP53 mutations, although only 20%-30% evoke anti-p53 AAbs.
Serum and tissue samples were analyzed from 174 patients with ovarian cancer who were included in the Danish Pelvic Mass/Gynecologic Ovarian Vulva Endometrial and Cervix Cancer study.
Elevated levels of immunoglobulin G anti-p53 AAbs were detected in 30 patients, all with HGSC. Among the patients who had HGSC, elevated levels of anti-p53 AAbs were identified in 17% of those with early stage (I-II) disease and in 23% of those with late stage (III + IV) disease. Ninety-seven percent of samples with elevated anti-p53 AAbs had TP53 mutations, 93% had mutations restricted to the DNA-binding domain, and 89% had overexpression of p53 protein in tissue sections. Neither anti-p53 AAb levels nor p53 protein expression was associated with survival. Infiltration of CD20-positive/CD23-positive B cells and CD8-positive T cells correlated with anti-p53 AAbs, consistent with heightened immune activation. Increased immunoglobulin production appeared to be specific for p53 in that no correlation was observed between anti-p53 AAbs and human epididymis protein 4 antigen-AAb complexes. Absorption experiments have suggested that anti-p53 AAbs associated with HGSC are directed against epitopes on wild-type p53 protein. TP53 mutation and overexpression of p53 appear to be necessary, but not sufficient, for the induction of anti-p53 AAbs.
Anti-p53 AAbs identify a distinct subset of TP53-mutant HGSC with an active tumor immune microenvironment and warrant further development as a biomarker for early detection.