Peripheral TNF-α and CD8+/CD28+ T Lymphocytes as Alternatives for PD-L1 Prediction in Breast Cancer Tumor Microenvironment: Stratified by Neoadjuvant Therapy.

Background: Programmed death-ligand 1 (PD-L1) is an immunotherapy target; however, its detection is based on biopsy tissues, and repeated biopsies present clinical challenges. This study aimed to explore peripheral blood-based alternatives to PD-L1 tissue detection in breast cancer (BC), particularly stratification by neoadjuvant therapy (NAT).

Methods: A total of 134 cases were recruited, the peripheral lymphocyte subtypes and cytokines were detected by flow cytometry and PD-L1 expression in tumor microenvironment (TME) was detected by immunohistochemistry and assessed by two qualified pathologists.

Results: The patients with positive PD-L1 expression had peripheral CD8⁺/CD28⁺ T lymphocytes 20% higher than those with negative expression (p = 0.008) with the area under the receiver operating characteristic curve (AUC) being 0.64 (p = 0.002). Among patients with negative NAT, positive PD-L1 expression was associated with peripheral CD8⁺/CD28⁺ T lymphocytes that increased by 54% (p = 0.003), and the AUC being 0.68 (p = 0.003). In patients receiving NAT, positive PD-L1 expression was associated with peripheral TNF-α (p = 0.010), which increased from 0.45pg/mL to 0.64pg/mL in the PD-L1 positive group, and the AUC was 0.79 (p = 0.012). Among patients without NAT experience, a 1% increase in peripheral CD8⁺/CD28⁺ T lymphocytes was associated with a 21% higher probability of positive PD-L1 expression (OR = 1.21, 95% CI: 1.06-1.37) and among patients with NAT, the OR of peripheral TNF-α (>0.5pg/mL) increased to 24.5 for positive TME PD-L1 expression (p = 0.008).

Conclusion: Peripheral CD8⁺/CD28⁺ T cell percentages and TNF-α levels served as non-invasive biomarkers for TME PD-L1 expression in BC patients with and without NAT, respectively. These biomarkers warranted further validation in clinical implementation to guide precision immunotherapy.