The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing Piece of the Puzzle for the Efficient Targeting of these Cells with Immunotherapy

Abstract

Cancer Stem Cells/Cancer Initiating Cells (CSCs/CICs) is a rare sub-population within a tumor that is responsible for tumor formation, progression and resistance to therapies. The interaction between CSCs/CICs and tumor microenvironment (TME) can sustain "stemness" properties and promote their survival and plasticity. This cross-talk is also pivotal in regulating and modulating CSC/CIC properties. This review will provide an overview of the mechanisms underlying the mutual interaction between CSCs/CICs and TME. Particular focus will be dedicated to the immunological profile of CSCs/CICs and its role in orchestrating cancer immunosurveillance. Moreover, the available immunotherapy strategies that can target CSCs/CICs and of their possible implementation will be discussed. Overall, the dissection of the mechanisms regulating the CSC/CIC-TME interaction is warranted to understand the plasticity and immunoregulatory properties of stem-like tumor cells and to achieve complete eradications of tumors through the optimization of immunotherapy.

Cancer Stemness Meets Immunity: From Mechanism to Therapy

“…The second approach is to harness the potential of T-cell-based immunotherapies, especially immune checkpoint inhibition (ICI). The anti-tumor effectiveness of ICIs relates to the expression of immune checkpoint molecules, such as PD-L1, in the TME ( Ravindran et al, 2019 ). Following activation of the STAT3 and NOTCH3/mTOR pathways ( Lee et al, 2016 ; Mansour et al, 2020 ), CSCs express higher PD-L1 level compared to non-CSCs in many cancer types, including GBM, melanoma, SCCHN, CRC, breast cancer, gastric cancer, and ovarian cancer, in which PD-L1 can further promote CSC stemness, thus inducing a positive feedback loop ( Gao et al, 2019 ; Gupta et al, 2016 ; Ravindran et al, 2019 ; Wei et al, 2019a ).…”

Tumor-Infiltrating CD20+ B Lymphocytes: Significance and Prognostic Implications in Oral Cancer Microenvironment

“…However, inflammation in OSCCs has been generally associated with poor survival [ 6 ]. Necrosed tumor cells may contribute to an inflamed TME and also proinflammatory cytokines released by CSCs, such as IL-6, IL-8, IL-10, and IL-13 can contribute to maintaining an inflammatory and suppressive TME representing the “niche” sustaining cellular stemness [ 68 ].…”

Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective

“…This represents a mechanism of immune evasion that is shared with normal stem cells. [ 31 , 32 ]. Further, ABCB5+ melanoma CSCs preferentially inhibited IL-2–dependent T-cell activation in a CD86-dependent manner and induced CD4+CD25+FoxP3+ regulatory T cells (T-regs) [ 33 ].…”