The Human Leukocyte Antigen G as an Immune Escape Mechanism and Novel Therapeutic Target in Urological Tumors.

Simon Jasinski-Bergner,Christian Fiebig,Barbara Seliger,Helge Taubert,Sven Wach,Arndt Hartmann,Markus Eckstein,Reiner Strick

doi:10.3389/fimmu.2022.811200

Abstract

The non-classical human leukocyte antigen G (HLA-G) is a potent regulatory protein involved in the induction of immunological tolerance. This is based on the binding of membrane-bound as well as soluble HLA-G to inhibitory receptors expressed on various immune effector cells, in particular NK cells and T cells, leading to their attenuated functions. Despite its restricted expression on immune-privileged tissues under physiological conditions, HLA-G expression has been frequently detected in solid and hematopoietic malignancies including urological cancers, such as renal cell and urothelial bladder carcinoma and has been associated with progression of urological cancers and poor outcome of patients: HLA-G expression protects tumor cells from anti-tumor immunity upon interaction with its inhibitory receptors by modulating both the phenotype and function of immune cells leading to immune evasion. This review will discuss the expression, regulation, functional and clinical relevance of HLA-G expression in urological tumors as well as its use as a putative biomarker and/or potential therapeutic target for the treatment of renal cell carcinoma as well as urothelial bladder cancer.

Highlights

During the last two decades it has been generally accepted that altered immune responses and immune evasion strategies are characteristic hallmarks of cancer
Defects of immune sensing mediated by the expression of inhibitory immune checkpoint receptors (ICP-R), such as e.g. the program death-1 receptor (PD-1), the CTLassociated antigen-4 (CTLA-4), T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin 3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA) and the lymphocyte activation gene (LAG-3) expressed on T and/or natural killer (NK) cells, represent so far known major immune escape mechanisms [5, 6]
This observation might be interesting for cancer entities, where human leukocyte antigen (HLA)-G neoexpression has been associated with concomitant high immune infiltration levels, such as Ewing sarcoma and Renal cell carcinoma (RCC) [140]

Summary

INTRODUCTION

During the last two decades it has been generally accepted that altered immune responses and immune evasion strategies are characteristic hallmarks of cancer. Based on the histology several RCC subtypes were classified, with

References breast cancer

Findings

CONCLUSIONS