J Pathol Transl Med.  2019 Mar;53(2):75-85. 10.4132/jptm.2018.10.11.

Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer

• Park HS
• Cho U
• Im SY
• Yoo CY
• Jung JH
• Suh YJ
• Choi HJ

• KMID: 2465446
• DOI: http://doi.org/10.4132/jptm.2018.10.11

Abstract

BACKGROUND
Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear.
METHODS
We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed.
RESULTS
Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II-IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I-positive tumors than in HLA-I-negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort.
CONCLUSIONS
Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.

Keyword

Breast neoplasms; HLA antigens; Major histocompatibility complex; Lymphocytes, tumor-infiltrating; T-lymphocytes, regulatory

MeSH Terms

Breast Neoplasms*
Breast*
Cohort Studies
HLA Antigens
Humans*
Immune Evasion
Immunohistochemistry
Immunotherapy
Leukocytes*
Lymphocytes, Tumor-Infiltrating
Major Histocompatibility Complex
Prognosis*
T-Lymphocytes, Regulatory
HLA Antigens

Figure

• 

  Fig. 1. Immunohistochemical staining of breast cancer tissues with anti–human leukocyte antigen class I (HLA-I) antibody. (A) Most of the HLA-I–positive cases showed a strong and diffuse membranous expression of HLA-I in breast cancer. In a HLA-I–positive case, the tumor cell membranes are completely stained with HLA-I. (B) A tumor with intermediate HLA-I expression (25%–75%) shows a heterogeneous staining pattern with a range of intensity. Partial loss of HLA-I expression in tumor cells is observed. (C) HLA-I–negative cases showed complete loss of HLA-I in breast cancer cells. Only the stromal cells are strongly stained and tumor cells are absent for HLA-I expression in cell membranes.

• 

  Fig. 2. The mean number of regulatory T lymphocytes in the human leukocyte antigen class I (HLA-I)–negative and HLA-I–positive tumors was 2.1 cells/high-power field (HPF) and 6.3 cells/HPF, respectively. There was a statistically significant difference in the regulatory T cell infiltration between the two groups (p<.001).

• 

  Fig. 3. (A) Disease-specific survival (DSS) of all patients with breast cancer based on human leukocyte antigen class I (HLA-I) expression (p=.029). (B) Disease-free survival (DFS) of all patients with breast cancer based on HLA-I expression (p=.863). (C) DSS of the patient subgroup with stage II–IV breast cancer based on HLA-I expression (p=.007). (D) DFS of the patient subgroup with stage II–IV breast cancer based on HLA-I expression (p=.506).

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