Mechanisms by which tumor cells evade the immune system have an important role in tumor growth, as emphasized by the cancer immunosurveillance theory.
1 Among these escape mechanisms, alterations in the expression of classical and non-classical human leukocyte antigen (HLA) classes I and II antigens on tumor cells are of a particular interest. These antigens have a crucial role in the induction of specific immune responses, and can modulate the interactions of natural killer (NK) cells and T cell subpopulations with their target cells.
2–4 The clinical relevance of HLA class I expression in oncology is evident from the finding that a reduced expression often correlates with a worse prognosis,
5–10 while the relevance of HLA class II expression in cancer remains ambivalent.
1,11,12
Unlike most tumors, in uveal melanoma a high HLA class I expression is considered to be a bad prognostic sign.
13–16 This observation may be explained by the role of NK cells. Tumors with high HLA class I expression are more resistant to destruction by NK cells, as these cells specifically kill cells that lack certain HLA class I antigens.
16–18 Metastases of primary uveal melanoma show a high HLA-A and B expression,
19 thus suggesting evasion of NK cells by the tumor is necessary in the development of metastases. In uveal melanoma, a high expression of HLA class II also is related to a bad prognosis.
15
A small, but growing number of studies have indicated that, apart from HLA expression, HLA polymorphisms mediate susceptibility to certain neoplastic diseases.
20,21 In several uveal melanoma studies an increased incidence of HLA-A32 has been found,
22–25 and another study revealed that patients with HLA-B40 died more often from metastases.
26 Nevertheless, a study on 235 cases could not confirm this association between HLA- B40 and metastasis; however, the study did find an association between HLA-B44 and metastasis before correction. Therefore, a role for HLA genotype in prognosis is not excluded.
27
Other important immunological parameters associated with prognosis in uveal melanoma are lymphocyte
28 and macrophage
29 infiltration. High numbers of tumor-infiltrating CD68
+ and CD163
+ macrophages are associated with an unfavorable prognosis,
29–31 and CD68
+ macrophages have been associated with increased HLA classes I and II expression as well.
32 Several specific associations are known between HLA antigens and ocular diseases. It may well be that certain local immune responses may protect against the development of uveal melanoma by providing a local immunosurveillance system, for example against aberrant melanocytes. Choroidal autoimmune responses are noticed in birdshot chorioretinopathy (BCR), which is characterized by multiple hypopigmented chorioretinal lesions, and is associated with HLA-A29.
33 In Vogt-Koyanagi-Harada syndrome (VKH), a bilateral, chronic, diffuse panuveitis with late stage depigmentation of the fundus occurs, with a genetic association with primarily HLA-DR4.
34 Finally, uveitis in relation to autoimmune diseases has been related to HLA-B27.
35,36 Therefore, we investigated whether the most common as well as these specific HLA genotypes are related to the level of HLA expression on tumor cells and intra-tumoral macrophage infiltration, which can be regarded as parameters of inflammation in uveal melanoma.