Expression of HLA class I is associated with immune cell infiltration and patient outcome in breast cancer

Abstract

Downregulation of human leukocyte antigen (HLA) class I is one mechanism of escaping anti-tumor immunity by tumor cells. This study was conducted to compare HLA class I expression in ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC) and to evaluate its association with immune cell infiltration of the tumors and clinical outcome of the patients. A total of 830 cases comprising 288 DCIS and 542 IBC were included in this study. Immunohistochemistry for HLA class I expression was performed using HLA-ABC in tissue microarrays and was analyzed in relation to clinicopathologic characteristics of tumors and infiltration of CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells. As a whole, there was no difference in HLA class I expression between DCIS and IBC when dichotomized into high or low expression. However, in the HR-negative group, a high level of HLA class I expression was more frequent in IBC than DCIS. On the contrary, in the HR-positive group, a complete loss of HLA class I expression was more frequently observed in IBC than DCIS. High HLA class I expression level was generally associated with aggressive clinicopathologic features of IBC and was associated with high CD4+, CD8+, and FOXP3+ TIL and PD-L1+ immune cell infiltration in both DCIS and IBC. In survival analyses, HLA class I expression was not associated with clinical outcome in DCIS and IBC as a whole; however, low HLA class I expression was associated with poor clinical outcome in HR-negative IBC, especially in triple-negative subtype. In conclusion, this study showed that HLA class I expression increased in association with increased immune cell infiltration during in situ to invasive transition of HR-negative breast cancer, and HLA class I down-regulation had a prognostic value in HR-negative breast cancer.

Identification of RNA-binding protein hnRNP C targeting the 3’UTR of the TAP-associated glycoprotein tapasin in melanoma

“…In addition, in breast and lung cancer, the loss of HLA-I and associated molecules significantly correlated with a reduced number of tumor infiltrating T lymphocytes, 41 while high HLA-I expression levels were associated with an increased immune cell infiltration. 42 Since the HLA-I pathway inhibition by hnRNP C overexpression might affect the immune cell infiltration in melanoma cells, the correlation between hnRNP C expression and immune cell infiltration was investigated using 67 metastatic melanoma cases from the TCGA-SKCM dataset, which were divided into hnRNP C high and hnRNP C low expressors. It is well established that CD8 + T cells recognize antigens presented by HLA-I, 43 and HLA-I expression affects CD8 + T cell activation and is associated with the level of T cell infiltration.…”

Assessment of cancer cell‐expressed HLA class I molecules and their immunopathological implications

“…Although it is generally believed that cancers with decreased HLA class I expression have less lymphocytic infiltration, colorectal cancers exceptionally have more lymphocytic infiltration even when HLA class I expression is decreased. 93,94,[132][133][134][135] Various explanations have been proposed for this phenomenon. In colorectal cancer, γδ T cells have been shown to have a possible anticancer effect.…”

“…As mentioned earlier, HLA class I molecules tend to be downregulated in dMMR patients with colorectal cancer, who are more likely to respond to ICIs. Although it is generally believed that cancers with decreased HLA class I expression have less lymphocytic infiltration, colorectal cancers exceptionally have more lymphocytic infiltration even when HLA class I expression is decreased 93,94,132–135 . Various explanations have been proposed for this phenomenon.…”

“…HLA class I expression in the cancer cells assessed by immunostaining is associated with prognosis in clinical samples from various malignancies. Representative studies showing the prognostic significance of HLA class I expression in tumors evaluated by immunohistochemistry using FFPE specimens are summarized in Table 1 49–51,55–114 . Many studies have concluded that the loss of HLA class I heavy chain expression is correlated with a worse prognosis, although some studies did not.…”