Tumor-Infiltrating Immunosuppressive Cells in Cancer-Cell Plasticity, Tumor Progression and Therapy Response

Abstract

In most tumors, cancer cells show the ability to dynamically transit from a non-cancer stem-like cell to a cancer stem-like cell (CSC) state and vice versa. This cell plasticity has been associated with the epithelial-to-mesenchymal transition program (EMT) and can be regulated by tumor cell-intrinsic mechanisms and complex interactions with various tumor microenvironment (TME) components. These interactions favor the generation of a specific "CSC niche" that helps maintain the main properties, phenotypic plasticity and metastatic potential of this subset of tumor cells. For this reason, TME has been recognized as an important promoter of tumor progression and therapy resistance. Tumors have evolved a network of immunosuppressive mechanisms that limits the cytotoxic T cell response to cancer cells. Some key players in this network are tumor-associated macrophages, myeloidderived suppressor cells and regulatory T cells, which not only favor a pro-tumoral and immunosuppressive environment that supports tumor growth and immune evasion, but also negatively influences immunotherapy. Here, we review the relevance of cytokines and growth factors provided by immunosuppressive immune cells in regulating cancer-cell plasticity. We also discuss how cancer cells remodel their own niche to promote proliferation, stemness and EMT, and escape immune surveillance. A better understanding of CSC-TME crosstalk signaling will enable the development of effective targeted or immune therapies that block tumor growth and metastasis.

CXCR4 Inhibition Counteracts Immunosuppressive Properties of Metastatic NSCLC Stem Cells

“…The subset of CSCs deputed to metastasis initiation possesses features allowing primary tumor escape, survival in circulation, and distant organs seeding ( 50 , 51 ). Immune escape mechanisms adopted by MICs are supposed to be essential to complete all the steps leading to metastasis generation ( 52 , 53 ).…”

“…Some evidence has reported that CSCs are characterized by specific immunological properties, which protect them against chemotherapeutic drugs but also increase their resistance toward apoptosis-inducing immune effectors, like T or NK cells ( 54 ). Several mechanisms can be exploited by CSCs to escape immune surveillance, such as down-regulation of MHC class I and II molecules, inefficient antigen presentation, and release of immunosuppressive factors ( 52 ). These strategies would help CSCs to survive, sustain tumor progression, and metastasize ( 53 ).…”

“…Moreover, it has been reported that there is a correlation between immunosuppressive environment and activation of epithelial to mesenchymal transition (EMT) program, endowing primary tumor cells with disseminating and stemness properties ( 52 , 55 ). Dongre et al.…”

Macrophage-Based Approaches for Cancer Immunotherapy

“…Engineered lymphocytes have to traverse abnormal tumor vasculature with reduced adhesion molecules, experience chemokine/chemokine receptor mismatch (8), and must migrate through dense cellular and stromal barriers. Upon ingress into the TME, effector cells encounter unfavorable conditions such as a hypoxic and acidic environment (9), expression of immune checkpoint ligands (10,11), and an abundance of immunosuppressive cells such as tumor associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs), and regulatory T cells (T-regs) (12). Additionally, chronic antigen engagement can lead to T cell exhaustion, decreasing the effector function of CAR T cells (13).…”

Immune cell infiltration and cytokine secretion analysis reveal a non-inflammatory microenvironment of medulloblastoma

“…Immunotherapy is effective for patients with melanoma, leukemia and other solid tumors ( 7 – 10 ). The importance of lymphocytes and tumor-associated macrophages (TAMs) in the tumor microenvironment has been assessed and is considered a key factor of immunotherapy response ( 11 , 12 ). However, little is known about the comprehensive immune infiltration in brain tumor, particularly in MB.…”