New Insights Into the Role of Qa-2 and HLA-G Non-classical MHC-I Complexes in Malignancy

Abstract

It is well established that the immune system can identify and destroy neoplastic transformed cells in a process known as immunosurveillance. Most studies have focused on the classical major histocompatibility complex (MHC) class Ia molecules, which are known to play an important role on the presentation of tumor antigens to the immune system in order to activate a response against tumor cells. However, a larger family of non-classical MHC class Ib-related molecules has received less attention. In this mini-review, we discuss the role of class Ib murine Qa-2 and its proposed human HLA-G homolog on immunosurveillance during embryogenesis and cancer. Whereas, both HLA-G and Qa-2 are involved in immune tolerance in pregnancy, the current evidence suggests that they play opposite roles in cancer. HLA-G appears to promote tumor progression while Qa-2 acts as a tumor suppressor awaking the immune system to reject tumor cells, as suggested by studies on different cancer cell models, such as melanoma, lymphoma, lung carcinoma, and our own results in mammary carcinoma.

Keywords: HLA-G; MHC-I; Qa-2; cancer; immunosurveillance.

Figure 1

Functions of HLA-G and Qa-2 on immune cells in the tumor microenvironment. HLA-G, either on the surface of tumor cells or in its soluble form or associated with exosomes, inhibits different traits of immune cells through interaction with the inhibitory receptors ILT2 and ILT4, allowing tumor cells to escape from immune surveillance. Also, HLA-G has been reported to interact with KIR2DL4 receptor to activate NK cells, although this is a matter of controversy (see the text). On the other hand, Qa-2 has been reported to activate NK cells and CD8⁺ CTLs that inhibit tumor cell growth and mediate tumor rejection. Inhibition of NK cells by Qa-2 was also reported in vitro, and Ly49C postulated as a Qa-2 inhibitory receptor, see the text. Receptors on immune cells involved in the response to Qa-2 are presently unknown. Likewise, whether Qa-2 is released to the extracellular milieu associated to exosomes remains to be investigated.