(Im)maturity in Tumor Ecosystem

Abstract

Tumors have special features that make them distinct from their normal counterparts. Immature cells in a tumor mass and their critical contributions to the tumorigenesis will open new windows toward cancer therapy. Incomplete cellular development brings versatile and unique functionality in the cellular tumor ecosystem, such as what is seen for highly potential embryonic cells. There is evidence that maturation of certain types of cells in this ecosystem can recover the sensitivity of the tumor. Therefore, understanding more about the mechanisms that contributed to this immaturity will render new therapeutic approaches in cancer therapy. Targeting such mechanisms can be exploited as a supplementary to the current immunotherapeutic treatment schedules, such as immune checkpoint inhibitor (ICI) therapy. The key focus of this review is to discuss the impact of (im)maturity in cellular tumor ecosystems on cancer progression, focusing mainly on immaturity in the immune cell compartment of the tumor, as well as on the stemness of tumor cells.

Keywords: dendritic cell (DC); immaturity; immune checkpoint; immunity; myeloid-derived suppressor cell (MDSC); natural killer (NK); programmed death-ligand 1 (PD-L1); stemness.

Figure 1

Tumors at the interface of a poorly differentiated embryonic progeny and terminally differentiated body organs. Tumors are organ-like structures that represent a pack of immature cell types, which bring them higher capacities to promote resistance, relapse, and metastasis. A tumor closer to the embryonic progeny displays higher progressive potency, whereas a more differentiated cellular state in a tumor will bring higher sensitivity to therapy.

Figure 2

Interactions among immune cells for promoting maturity/immaturity within the tumor immune ecosystem. Maturation of dendritic cells (DCs) is affected positively from the impact of natural killer (NK) cells, but negatively affected from the effects of cancer cells, regulatory T (Treg) cells, and myeloid-derived suppressor cells (MDSCs). Interleukin-10 (IL-10), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and vascular endothelial growth factor (VEGF) are inhibitory factors released from cancer cells, Tregs, and MDSCs, respectively. IL-10 is also released from MDSCs and macrophage type 2 (M2) cells. Tregs impede DC maturation through CTLA-4 and IL-35. Immature DCs are signal transducer and activator of transcription 6 (STAT6)⁺ and take tumor-promoting activities, mediated via enhancing Treg proliferation and stimulating T cell anergy. By contrast, mature DCs are STAT1⁺ and stimulate CD8⁺ T cell priming and NK cell effector function. Cancer cells release high levels of prostaglandin E2 (PGE2) upon exposure to hypoxia. PGE2 hampers maturation of NK cells. By contrast, maturation of NK cells is promoted by IL-15, released from DCs and M1 cells. NK cells further release IL-21 for promoting stem-like memory CD8⁺ T cells.

Figure 3

The impact of (im)maturity on final functional state in tumor immune ecosystem. Natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in a mature cellular state will strengthen immune proficiency against cancer. Stem-like immune niches exist in tumors, strengthening of which will lead to the more effective cancer immunotherapy. Monocytes and neutrophils in an immature state will form myeloid-derived suppressor cells (MDSCs), which act as strong suppressors of the immune system. Similarly, immature endothelial cells (ECs) form aberrant vasculature, which aids tumor progression and relapse. This is also inferable for mesenchymal (M⁺) tumor cells (cancer stem cells [CSC] in particular) that represent high resistance and tumor-promoting activities. This contrasts with cells with epithelial-like (E⁺) phenotype. *Antigen-presenting cells (APCs) including DCs and macrophages.

Figure 4

Mediators of (im)immaturity. Vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, programmed death ligand-1 (PD-L1), and epithelial-mesenchymal transition (EMT) are mediators of immaturity that contribute to the tumor progression and relapse. By contrast, agents like all-trans retinoic acid (ATRA), granulocyte-macrophage colony stimulating factor (GM-CSF), and TNF-related apoptosis induced ligand-receptor2 (TRAIL-R2) are mediators of maturity that are contributed to cellular differentiation. Agonists of maturity mediators can be an appropriate supplement in the area of immunotherapy. Controversies, however, exist for the use of GM-CSF, which require more research in the area. DC, dendritic cell; MDSC, myeloid-derived suppressor cell; and mAb, monoclonal antibody. *DS-8273a is a TRAIL-R2 agonist.