Abstract
Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.
Highlights
Immune suppressive functions induced by the interaction between human leukocyte antigen-G (HLA-G) and its immune inhibitory receptors, the immunoglobulin-like transcripts (ILTs), have been widely acknowledged [1]
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Anti-HLA-G antibodies were divided into two HLA-G Antibodies and
Summary
Immune suppressive functions induced by the interaction between human leukocyte antigen-G (HLA-G) and its immune inhibitory receptors, the immunoglobulin-like transcripts (ILTs), have been widely acknowledged [1]. Look back to its expression firstly observed in cancer, the melanoma lesions in 1998 [5], immune tolerance induced by HLA-G has been solidified by large numbers of studies both in vitro and in vivo preclinical experimental animal models [6,7,8]. HLA-G/ILTs binding can inhibit the proliferation of natural killer cells (NK), T and B lymphocytes and maturation and antigen presentation of dendritic cells (DC), suppress NK and T cell’s cytotoxic function, B cell’s immunoglobulin production and neutrophils’ reactive oxygen species production and phagocytosis capability [9,10,11]. HLA-G/ILTs binding can promote myeloid-derived suppressor cells (MDSC) proliferation and polarize M1 macrophages towards to M2 type [12, 13]
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