The ratio of CD8 + lymphocytes to tumor-infiltrating suppressive FOXP3 + effector regulatory T cells is associated with treatment response in invasive breast cancer

Noriko Goda; Shinsuke Sasada; Hideo Shigematsu; Norio Masumoto; Koji Arihiro; Hiroyoshi Nishikawa; Shimon Sakaguchi; Morihito Okada; Takayuki Kadoya

doi:10.1007/s12672-022-00482-5

The ratio of CD8 + lymphocytes to tumor-infiltrating suppressive FOXP3 + effector regulatory T cells is associated with treatment response in invasive breast cancer

Discov Oncol. 2022 Apr 19;13(1):27. doi: 10.1007/s12672-022-00482-5.

Authors

Noriko Goda¹, Shinsuke Sasada¹, Hideo Shigematsu², Norio Masumoto¹, Koji Arihiro³, Hiroyoshi Nishikawa^{4

5}, Shimon Sakaguchi⁶, Morihito Okada¹, Takayuki Kadoya⁷

Affiliations

¹ Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
² Department of Breast Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
³ Department of Anatomical Pathology, Hiroshima University, Hiroshima, Japan.
⁴ Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
⁵ Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶ Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
⁷ Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. takayukikadoya@gmail.com.

Abstract

Purpose: FOXP3 + and CD8 + are recognized markers of tumor-infiltrating lymphocytes (TILs) for breast cancer. FOXP3 + TILs are composed of effector Tregs (eTregs) and other subpopulations that are classified by their differences in suppressive function. In this prospective study, we evaluated Treg subpopulations and CD8 + TILs in breast cancer.

Methods: 84 patients with breast cancer were enrolled. Fresh TILs were extracted andTregs were classified into eTregs (CD4⁺FOXP3^highCD45RA^-), other FOXP3⁺ Treg subsets (naïve and non-Tregs), and total CD8⁺CD4^- TILs using flow cytometry. The suppression strength of each Treg subpopulation was analyzed. The association between TIL subpopulations, clinicopathological characteristics, and response to chemotherapy was evaluated.

Results: The mean CD8/eTreg ratio value was 7.86 (interquartile range: 4.08-12.80). The proliferation function of eTregs was significantly suppressed compared with that of the other subpopulations (proliferation rates: control: 89.3%, + naiiveTreg: 64.2%, + non-Treg: 78.2% vs eTreg 1.93%; all P < 0.05). The patients with high with a high CD8 + /eTreg ratio achieved excellent pathological complete response (pCR) rate of neoadjuvant chemotherapy (90.2%) and the CD8/eTreg ratio were independent predictive factors for pCR (odds ratio:18.7(confidence interval 1.25-279) P < 0.05). A detailed assessment of the CD8/eTreg ratio for each patient who underwent NAC revealed that high CD8/eTreg ratio showed a significantly higher pCR rate compared to patients with a low CD8/FOXP3 ratio (39.6% vs 13.3, P < 0.05) in triple negative subtype patients with stromal TILs < 50%.

Conclusions: A high CD8/eTreg ratio enhances pCR rate in patients with invasive breast cancer.

Keywords: Breast cancer; CD8; FOXP3; Neoadjuvant chemotherapy; Regulatory T cell; Tumor-infiltrating lymphocyte.