The transition from HLA-I positive to HLA-I negative primary tumors: the road to escape from T-cell responses.

MHC/HLA class I loss in cancer is one of the main mechanisms of tumor immune escape from T-cell recognition and destruction. Tumor infiltration by T lymphocytes (TILs) and by other immune cells was first described many years ago, but has never been directly and clearly linked to the destruction of HLA-I positive and selection of HLA-I negative tumor cells. The degree and the pattern of lymphocyte infiltration in a tumor nest may depend on antigenicity and the developmental stages of the tumors. In addition, it is becoming evident that HLA-I expression and tumor infiltration have a direct correlation with tumor tissue reorganization. We observed that at early stages (permissive Phase I) tumors are heterogeneous, with both HLA-I positive and HLA-negative cancer cells, and are infiltrated by TILs and M1 macrophages as a part of an active anti-tumor Th1 response. At later stages (encapsulated Phase II), tumor nests are mostly HLA-I negative with immune cells residing in the peri-tumoral stroma, which forms a granuloma-like encapsulated tissue structure. All these tumor characteristics, including tumor HLA-I expression pattern, have an important clinical prognostic value and should be closely and routinely investigated in different types of cancer by immunologists and by pathologists. In this review we summarize our current viewpoint about the alterations in HLA-I expression in cancer and discuss how, when and why tumor HLA-I losses occur. We also provide evidence for the negative impact of tumor HLA-I loss in current cancer immunotherapies, with the focus on reversible ('soft') and irreversible ('hard') HLA-I defects.