Abstract
Tumor immune escape is associated with the loss of tumor HLA class I (HLA-I) expression commonly found in malignant cells. Accumulating evidence suggests that the efficacy of immunotherapy depends on the expression levels of HLA class I molecules on tumors cells. It also depends on the molecular mechanism underlying the loss of HLA expression, which could be reversible/“soft” or irreversible/“hard” due to genetic alterations in HLA, β2-microglobulin or IFN genes. Immune selection of HLA-I negative tumor cells harboring structural/irreversible alterations has been demonstrated after immunotherapy in cancer patients and in experimental cancer models. Here, we summarize recent findings indicating that tumor HLA-I loss also correlates with a reduced intra-tumor T cell infiltration and with a specific reorganization of tumor tissue. T cell immune selection of HLA-I negative tumors results in a clear separation between the stroma and the tumor parenchyma with leucocytes, macrophages and other mononuclear cells restrained outside the tumor mass. Better understanding of the structural and functional changes taking place in the tumor microenvironment may help to overcome cancer immune escape and improve the efficacy of different immunotherapeutic strategies. We also underline the urgent need for designing strategies to enhance tumor HLA class I expression that could improve tumor rejection by cytotoxic T-lymphocytes (CTL).
Highlights
There is a general consensus among immunologists that tumor cells can be recognized and destroyed by CD8+ T lymphocytes in vitro and in vivo
Using a combination of flow cytometry and tumor tissue immunohistology, we found a considerable prevalence of activated CD8+DR+ T cells of effector-memory phenotype in tumor tissues (TT) as compared to TAT and distant non-tumor tissue (DNTT) areas
Our findings point to the existence of alternative immune mechanisms influencing cells, such as (a) difficulty of homing, which translates to the practical exclusion of such as (a) difficulty of homing, which translates to the practical exclusion of natural killer (NK) cells by cancer cells; NKacells by cancer cells; (b)ina progressive alteration in the phenotype of NK to cells fromtissue, healthy tissue (b) progressive alteration the phenotype of NK cells from healthy tissue tumor with the to tumor tissue, with the emergence ofina tumor non-cytotoxic in tumoroftissue, we found emergence of a non-cytotoxic phenotype; tissue, wephenotype; found a prevalence
Summary
There is a general consensus among immunologists that tumor cells can be recognized and destroyed by CD8+ T lymphocytes in vitro and in vivo. Different tumor-immune escape mechanisms have been described that could explain the paradox of the absence of a CTL-mediated tumor rejection and the existence of tumor peptides recognized by CD8+ T cells [5]. If the molecular mechanism is irreversible/“hard”, caused by mutations or Loss of Heterozygosity (LOH) in chromosomes 6 or 15, tumor cells are likely to remain HLA-I negative and subsequently escape immune rejection. This review summarizes these findings, focusing on the newly described association between tumor “rejection” or “escape” phenotypes and corresponding changes observed in tumor tissue architecture
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