Cancer resistance to immunotherapy: What is the role of cancer stem cells?

Abstract

Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.

Keywords: Immunotherapy; cancer stem cells; immunotherapy resistance; tumor microenvironment.

Figure 1

CSC-mediated immune escape and self-renewal. The tumor microenvironment is home to a lot of immune cells, which contribute to cancer cell survival and proliferation. The CSCs can self-renew themselves due to their stem-like properties and are also aided by different cytokines in the TME. Metabolic products from the CSCs, such as retinoic acid and lactate, are also involved in their self-renewal. Other immune cells in the TME, such as MDSCs, immature neutrophils, and TAMs, are also involved in tumor proliferation by dampening the cytotoxic effects of killer T cells and promoting regulatory T cells. CSCs: Cancer stem cells; TME: tumor microenvironment; TAMs: tumor-associated macrophages; CTL: cytotoxic T lymphocyte; Mac: macrophage; Mono: monocyte; Neu: neutrophil; DC: dendritic cells; Treg: regulatory T cell.