HLA antigen and NK cell activating ligand expression in malignant cells: a story of loss or acquisition

Abstract

Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non-classical HLA class I antigen and/or NKCAL expression. In contrast to these assumptions, experimental evidence suggests that in some cases dysplastic and malignant cells can acquire classical HLA class I antigen expression and/or lose the ability to express HLA class II antigens. In light of the latter findings as well as of the revival of the cancer immune surveillance theory, a reevaluation of the interpretation of changes in HLA antigen and NKCAL expression in malignant lesions is warranted. In this article, we first briefly describe the conventional types of changes in HLA antigen and NKCAL expression that have been identified in malignant cells to date. Second, we discuss the evidence indicating that, in at least some cell types, classical HLA class I antigen expression can be acquired and/or the ability to express HLA class II antigens is lost. Third, we review the available evidence for the role of immune selective pressure in the generation of malignant lesions with changes in HLA antigen expression. This information contributes to our understanding of the role of the immune system in the control of tumor development and to the optimization of the design of immunotherapeutic strategies for the treatment of cancer.

Fig. 1

Molecular mechanisms underlying the functional properties of HLA antigen and NKCAL expressed by malignant cells. Once the classical HLA class I-β₂m-peptide complex is transported to the plasma membrane, it plays a major role in the interactions between target cells and (a) activation of peptide-specific CTL through TCR; and (b) inhibition of T-cell subpopulations through inhibitory receptors KIR. In contrast to classical HLA class I antigens, the non-classical HLA class I antigens, HLA-G, inhibit CTL, CD4(+) T cells and NK cells through their interaction with the NK cells receptor CD94/NKG2. HLA class II expression by tumor cells may be potentially beneficial to TA-specific immune responses through their interaction with CD4(+) T cells, resulting in the activation of CD4(+) T-cell-mediated killing, macrophage through release of Th1 cytokines; B cells and eosinophils through release of Th2 cytokines, and CTL through release of Th1 cytokines

Fig. 2

Frequency of classical HLA class I antigen downregulation and HLA class II antigen expression in malignant lesions of different embryological origin. Solid tumors for which more than 50 primary lesions have been analyzed for a classical and b HLA class II expression are shown. BCC cutaneous basal cell carcinoma, ESO esophageal carcinoma, HNSCC head and neck squamous cell carcinoma, MM malignant melanoma, OV ovarian carcinoma, RCC renal cell carcinoma, SCC squamous cell carcinoma, UM uveal melanoma

Fig. 3

Frequency of non-classical HLA class I antigen, HLA-G, expression in malignant lesions of different embryological origin. Solid tumors for which more than 50 primary lesions have been analyzed for non-classical HLA class I antigen, HLA-G, expression are shown. NHL non-Hodgkin’s lymphoma, RCC renal cell carcinoma

Fig. 4

Differential HLA antigen expression in benign and atypical melanocytic nevi, in cutaneous melanoma and in surrounding normal cells. a Only normal keratinocytes, endothelial cells, and antigen-presenting cells were marked by HLA class I heavy chain-specific mAb HC-10 in the immunoperoxidase reaction in an intradermal nevus (×10). b Normal keratinocytes, endothelial cells, antigen-presenting cells, and melanocytes were marked by HLA class I heavy chain-specific mAb HC-10 in the immunoperoxidase reaction in a severely atypical nevus (×10). c Normal keratinocytes, endothelial cells, and malignant melanocytes but not intradermal nested melanocytes or vertical growth phase melanoma cells were marked by HLA class I heavy chain-specific mAb HC-10 in the immunoperoxidase reaction in a superficial spreading melanoma arising within an intradermal nevus (×10)

Fig. 5

Immunoselection and microevolution of tumors. Tumor evolution is thought to adhere to Darwinian principles by escaping both non-immune (intrinsic) and immune (extrinsic) responses against self-altered malignant cells. Pre-malignant cells that acquire genetic mutations may undergo apoptosis or in parallel, acquire the expression of HLA as well as NKCAL through intrinsic cell-cycle control or DNA damage response mechanisms. Those cells resistant to apoptosis may be targeted by the host’s immune system. The type of immune response elicited by each tumor is most likely dependent upon a number of factors including the etiology of the tumor, patient characteristics as well as tumor microenvironment. During this immune response, the selective pressure facilitates the outgrowth of tumor cells that have lost the molecule(s) targeted by the ongoing immune response. Equilibrium most likely develops between the tumor cell escape variants and the adapting host’s immune response. At some point, the immune response is unable to adapt to the changing tumor cell population resulting in tumor growth. It is noteworthy that a cause–effect relationship between multiple rounds of immune selection and the appearance of multiple HLA or NKCAL abnormalities has not been proved yet. Nevertheless, if correct, our view about the role of immune selection in the generation of a malignant cell phenotype implies that a tumor will grow only when it has developed enough escape mechanisms to avoid the range of immune responses a patient’s immune system is able to mount