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Immunomodulating and Immunoresistance Properties of Cancer-Initiating Cells: Implications for the Clinical Success of Immunotherapy

ABSTRACT Cancer-initiating cells (CICs) represent a relatively rare subpopulation of cells endowed with self-renewal, stemness properties, tumorigenicity in immunodeficient mice, and resistance to standard therapies as well as to immunotherapy. Here, we review the biological and immunological characteristics of CICs with special focus on the immunomodulating mechanisms they utilize to escape from immunosurveillance. The recently developed immunotherapeutic strategies have yielded remarkable clinical results in many types of tumors, indicating that indeed a patient’s immune system can mount an immune response, which is effective in controlling tumor growth. However, a high proportion of patients is resistant or acquires resistance to these therapeutic strategies. The latter findings may reflect, at least in some cases, the inability of the immunotherapeutic strategies used to eradicate CICs. The CICs that escape immune recognition and destruction may give rise to new tumors in the same organ site or through the metastatic colonization in other anatomic sites. Identification of novel therapeutic approaches that can eradicate CICs is a major challenge in the cancer therapy area. An improved understanding of the interactions of CICs with immune system and with tumor microenvironment may contribute to optimize the available therapies and to design novel combination treatments for cancer therapy. Abbreviations: ALDH, aldehyde dehydrogenase; APC, antigen-presenting cells; APM, antigen-processing machinery; CAR: chimeric antigen receptor; CHK1, checkpoint serine/threonine protein kinase; CIC, cancer-initiating cell; CRC, colorectal cancer; CTLA-4, cytotoxic T lymphocyte antigen-4; GBM, glioblastoma multiforme; GDF-15, growth differentiation factor-15; CSPG4: chondroitin sulfate proteoglycan-4; IFN, interferon; IL-4, interleukin-4; IL-10, interleukin-10; IL-13, interleukin-13; IL-13α2, α2 chain of IL-13 receptor; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1 programmed death ligand-1; PDK, 3-phosphoinositide-dependent protein kinase-1; PGE2, prostaglandin E2; STAT3, signal transducer and activator of transcription 3; TGFB-1, transforming growth factor beta-1; Treg, T regulatory cell.