Understanding the tumor immune escape and the immune modulatory function of cancer stem cells

Cancer therapy is experiencing a paradigm shift due to the clinical success of immune checkpoint inhibitors (ICI), yet efficacy remains limited to a few tumor types and a minority of patients. In an increasing number of cancers, tumor populations called cancer stem cells (CSCs) or tumor-initiating cells (TIC) have been defined. Strong evidence is supporting the immunoresistance feature of CSCs. CSCs can also assist immunosuppression in the Tumor microenvironment (TME) through interaction with other tumor stroma cells. Understanding the mechanisms leading to the immunotolerance of CSCs will be essential for treatment of immune-resistant and metastatic tumors. The identification of such mechanisms faces challenges when applying the widely used transplanted tumor models since they fail to recapitulate the tumor microenvironment as it develops during the progression of human tumors. We previously generated a transgenic model of autochthonous melanoma, named TiRP, which express murine MAGE-type antigen P1A, and can be used as a more faithful preclinical model for immunotherapy. In this model, the CSCs and CTCs are immune resistant. They are devoid of surface MHC I expression and are resistant to both antigen-specific T-cells-and NK-cells-mediated killing. In contrast to non-CSC tumor clones from the TiRP tumor (T429.11), CSCs/CTCs, when transplanted into recipient mice, generate a highly immunosuppressive TME with high numbers of PMN-and Monocytic-MDSCs, and are resistant to immune therapy.