The environment encircling tumors, known as the tumor microenvironment (TME), represents a complex and dynamic ecosystem pivotal to the growth and advancement of cancer. Immune cells occupy a central stage within this complex milieu, assuming dual roles that can either foster or impede the proliferation of malignant cells.
Tumor Microenvironment
The TME is a diverse and intricate network of cells, extracellular matrix components, and signaling molecules that collectively influence cancer cell behavior. It is a battleground where cancer cells interact with stromal cells, immune cells, and blood vessels. This ever-evolving setting significantly influences the trajectory of tumor development, the efficacy of treatment responses, and ultimately, the well-being of patients.
Fig.1 TME in anti- and pro-tumour conditions (Peña-Romero A. C., Orenes-Piñero E. 2022).
Immune Cells in the Tumor Microenvironment
Amidst the intricate tapestry of the tumor microenvironment (TME), an ensemble of immune cells including macrophages, T cells, B cells, NK cells, neutrophils, and their counterparts actively engage in orchestrating the anti-tumor immune response. Their dynamic interplay within the TME not only influences this microenvironment but also intricately regulates the trajectory of tumor growth and the insidious process of metastasis. Delving deeper, it becomes evident that within this TME, a complex interplay is established, governed by a myriad of factors such as tumor-derived cytokines, chemokines, and the nuanced interplay of metabolic conditions encompassing pH levels, oxygen concentrations, and the availability of vital nutrients. Consequently, depending on the intricate interplay of these factors within the TME, immune cells uniquely tailor their responses, thereby shaping the delicate balance between exerting either anti-tumor or pro-tumor effects.
Dendritic Cells in the TME
Dendritic cells, or DCs, are often referred to as the "sentinels" of the immune system. They are responsible for capturing and presenting antigens to T cells, thus initiating and regulating adaptive immune responses. In the TME, DCs are further classified into subsets, including cDC1s, cDC2s, pDCs, moDCs, and Langerhans cells, each with distinct functions.
Anti-Tumor Immunity by DCs
DCs are instrumental in initiating anti-tumor immune responses. They excel at cross-presenting tumor-derived antigens to CD8+ and CD4+ T cells, thus activating these cells to target cancerous cells. Co-stimulatory signals and activating cytokines contribute to the maintenance and enhancement of T cell function within tumors. Importantly, DCs release cytokines like interleukin-12 (IL-12), which induces interferon-gamma (IFN-γ) production by CD8+ T cells and activates natural killer (NK) cell-mediated cytotoxicity. Furthermore, they recruit other immune cells through activating cytokines, such as NK cells and effector T cells.
Pro-Tumor Influence of DCs
Despite their anti-tumor potential, DCs can also contribute to tumor progression. The TME can alter DCs' behavior, transforming them into immunosuppressive regulatory cells. Factors like IL-6 and IL-10 can negatively affect DC maturation, migration, and differentiation, promoting tumor immune evasion. Additionally, transforming growth factor-beta (TGF-β) can convert effector T cells into regulatory T cells (Tregs), creating an immunosuppressive environment.
Mast Cells in the TME
It is well-established that mast cells exert their influence through the secretion of a diverse array of factors, including but not limited to interleukins such as IL-1, IL-4, IL-6, IL-8, as well as TNF-α, IFN-γ, TGF-β, MCP-3, MCP-4, leukotriene B4 (LTB4), and proteases. These multifaceted substances can elicit responses that either foster inflammation, impede tumor cell proliferation, or trigger apoptosis in tumor cells.
Nevertheless, it is important to note that TAMCs, when prompted to promote tumor progression, have the capacity to augment the proliferation and viability of tumor cells. They accomplish this by discharging matrix metalloproteinases (MMPs), serine proteases, and various proteolytic enzymes, thereby facilitating tumor invasion and metastasis. In this particular context, intratumoral mast cells have been linked to unfavorable prognoses due to their pro-tumorigenic attributes.
Neutrophils in the TME
Numerous empirical investigations have unequivocally established the pivotal role of tumor-associated neutrophils (TANs) within the intricate milieu known as the tumor microenvironment (TME). These neutrophilic entities are characterized by their dynamic dichotomy, with certain subsets bearing anti-tumor properties. Indeed, a corpus of research endeavors has underscored the influential role of the TME in determining the equilibrium between N1 neutrophils, which harbor anti-tumor proclivities, and N2 neutrophils, endowed with pro-tumor inclinations. This dichotomy is exquisitely orchestrated by a repertoire of cytokines emanating from the TME, exemplified by transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and interleukin-35 (IL-35), all of which predispose TANs to adopt a pro-tumorigenic stance. Conversely, the anti-tumor polarization of TANs is facilitated by the presence of interferon-beta (IFN-β) and interleukin-12 (IL-12), underscoring the intricate interplay between TAN subtypes and their contextual cytokine milieu within the ever-evolving.
NK Cells in the TME
Natural killer (NK) cells, pivotal components of the immune system, orchestrate a multifaceted immune response marked by the secretion of a spectrum of cytokines and chemokines that include but are not limited to Interferon-gamma (IFN-γ), Interleukin-10 (IL-10), Interleukin-5 (IL-5), Interleukin-13 (IL-13), Tumor Necrosis Factor-alpha (TNF-α), and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). Notably, the intricate regulatory landscape of NK cell functionality is further enriched by the involvement of co-receptor molecules such as CD96, CD161, and CD244. These co-receptors wield the capacity to modulate cytokine production, thereby intricately shaping the NK cell-mediated immune response.
Amongst the panoply of cytokines secreted, IFN-γ stands out as one of the foremost. It emerges as a central protagonist in the context of NK cell's anti-tumor effector functions. This preeminent cytokine primarily carries out its mission through activation of the surface receptor NKG2D, orchestrating a formidable defense mechanism against malignant entities.
However, the narrative surrounding NK cells in the context of the intricate Tumor Microenvironment (TME) is marked by a nuanced duality. While they have garnered well-deserved recognition for their contributions to anti-tumor activities, NK cells are not immune to the sway of the TME, which exerts a profound influence aimed at subverting NK cell surveillance. The mechanisms by which NK cells are coerced into adopting a pro-tumor phenotype within the TME landscape are intrinsically linked to the machinations of immune editing and immune suppression. These regulatory maneuvers orchestrated within the TME framework pose formidable challenges to the unerring vigilance of NK cells, compelling them to navigate intricate terrain in their tireless quest to counteract tumorigenic processes.
The tumor microenvironment is a dynamic and multifaceted landscape where immune cells exert their influence, sometimes promoting anti-tumour immunity and other times fostering a pro-tumour environment. Understanding this duality is critical for developing targeted therapies that harness the power of the immune system while mitigating its potential drawbacks. Further research into the TME and its intricate interactions will continue to uncover new avenues for cancer treatment and immunotherapy.
Reference
- Peña-Romero A. C.; Orenes-Piñero E. Dual effect of immune cells within tumour microenvironment: pro-and anti-tumour effects and their triggers. Cancers. 2022, 14(7):1681.
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