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

Jiangping Wu,1,* Xin Ou,1,* Keyu Yuan,2 Feng Shi,3 Quan Zhou,4 Suzhen Lyu,2 Yanping Li,2 Yanjie Zhao,5 Yu Cao,1 Jianping Sun,1 Qingkun Song1,6 1Center of Clinical Epidemiology and Biobank, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Department of Breast Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 3Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 4Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, People’s Republic of China; 5Department of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 6Department of Clinical Epidemiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingkun Song, Center of Clinical Epidemiology and Biobank, Beijing Youan Hospital, Capital Medical University, Xitoutiao 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel +86-10-83997462, Email [email protected]: 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.Keywords: programmed death-ligand 1, T lymphocyte subtype, cytokine, neoadjuvant therapy, breast cancer