Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Intratumor heterogeneity among cancer cells is promoted by reversible or irreversible genetic alterations and by different microenvironmental factors. There is considerable experimental evidence of the presence of a variety of malignant cell clones with a wide diversity of major histocompatibility class I (MHC‐I) expression during early stages of tumor development. This variety of MHC‐I phenotypes may define the evolution of a particular tumor. Loss of MHC‐I molecules frequently results in immune escape of MHC‐negative or ‐deficient tumor cells from the host T cell‐mediated immune response. We review here the results obtained by our group and other researchers in animal models and humans, showing how MHC‐I intratumor heterogeneity may affect local oncogenicity and metastatic progression. In particular, we summarize the data obtained in an experimental mouse cancer model of a methylcholanthrene‐induced fibrosarcoma (GR9), in which isolated clones with different MHC‐I expression patterns demonstrated distinct local tumor growth rates and metastatic capacities. The observed “explosion of diversity” of MHC‐I phenotypes in primary tumor clones and the molecular mechanism (“hard”/irreversible or “soft”/reversible) responsible for a given MHC‐I alteration might determine not only the metastatic capacity of the cells but also their response to immunotherapy. We also illustrate the generation of further MHC heterogeneity during metastatic colonization and discuss different strategies to favor tumor rejection by counteracting MHC‐I loss. Finally, we highlight the role of MHC‐I genes in tumor dormancy and cell cycle control.