Increased PD-1 MRNA Expression in Peripheral Blood Cells of ER+ and PR+ Breast Cancer Patients and Its Unfavorable Prognostic Value

Abstract

Background: The clinical significance of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) expression on tumor infiltrating lymphocytes in breast cancer patients has been confirmed, while that of peripheral blood cells derived immune molecules remain unclear. Aim: We aimed to investigate the clinical importance of immune molecules, including PD-1 and CTLA-4, expression in peripheral blood cells of breast cancer patients, especially in terms of the relationship between immune molecules and estrogen receptor (ER)/progesterone receptor (PR) status, as well as their prognostic values. Methods: We enrolled 109 breast cancer patients, including 52 cases before surgery and neoadjuvant treatment (PreS group), 18 cases postsurgery and adjuvant chemoradiotherapy (PostS group), 39 metastatic cases presalvage treatment (Met group), and 21 age- and sex-matched healthy volunteers). The mRNA abundance of PD-1, CTLA-4, IL-2 receptor alpha (IL-2Rα), and cluster of differentiation 28 (CD28), forkhead box P3 (FOXP3), transforming growth factor beta (TGF-β), and interleukin-10 (IL-10) in pretreatment peripheral blood were analyzed by quantitative real-time PCR. Results: ER+ breast cancer patients showed significant higher mRNA levels of PD-1, CTLA-4, IL-2Rα, and CD28 with fold changes of 10.8, 2.4, 5.0, and 3.8, respectively ( P < 0.05) than that of ER− cases. Similarly, PR+ patients showed increased levels of PD-1, CTLA-4, and CD28 with fold changes of 6.7, 2.0, and 2.5, respectively ( P < 0.05) comparing to that of PR− cases. Patients in PreS group and Met group showed higher mRNA levels of PD-1, CTLA-4, IL-2Rα, CD28, FOXP3, TGF-β, and IL-10 than PostS group and healthy volunteers. Univariable analysis revealed that high PD-1 expression was associated with poorer progression-free survival (PFS) in metastatic breast cancer patients (5.9 vs 14.6 months, HR: 2.47, 95% CI: 1.22-5.02, P = 0.046). Meanwhile, the prognostic value of PD-1 was remained in multivariate analyses (HR: 2.22, 95% CI: 1.04-4.73, P = 0.039). Conclusion: Increased PD-1, CTLA-4, and CD28 mRNA abundance were showed in breast cancer patients and ER+/PR+ cases, which may provide the rationale for combining checkpoint inhibitors with endocrine therapy for breast cancer treatment. Furthermore, PD-1 is a promising prognostic biomarker for metastatic breast cancer.