A glance into tumor microenvironment

While reviewing a fascinating figure from Cell Science, Ghost came across an opportunity to discuss the tumor microenvironment (TME)—a dynamic battlefield where the tumor and the immune system continuously interact. The process of tumorigenesis, or the development of tumors, unfolds in distinct stages.

The Three Phases of Tumorigenesis

1. Immunosurveillance

In the initial phase, the immune system effectively suppresses tumor cells. Various immune effector cells, including T cells, natural killer (NK) cells, and certain macrophages, are recruited and activated to eliminate malignant cells.

2. Equilibrium

Some tumor cells succumb to immune attacks, while a small fraction survives by undergoing genetic changes. These surviving cells adapt and continue to challenge the immune system, leading to a prolonged struggle between immunity and tumor evolution.

3. Escape

Eventually, the tumor cells that have survived adapt by either genetically modifying themselves or by remodeling their microenvironment into an immune-suppressive niche. This enables them to evade immune surveillance and proliferate uncontrollably.

In summary, tumorigenesis shifts the tumor microenvironment from being immune-supportive to immune-suppressive, ultimately fostering tumor progression.

Tumor-Infiltrating Lymphocytes (TILs): Composition and Localization

Under an ideal immuno-oncology (IO) cycle, activated immune cells infiltrate the tumor tissue, collaborating to eliminate tumor cells. However, through genetic or epigenetic alterations, tumor cells can recruit a different set of immune cells, transforming the microenvironment into an immune-suppressive state. These alterations manifest as changes in TIL composition and localization.

Key Immune Cell Populations in the TME

Th1 vs. Th2

• Th1 (Type 1 Helper T Cells): Promote immune activation by secreting IFN-γ, which induces IL-12 production in dendritic cells (DCs) and macrophages, reinforcing a positive feedback loop. Th1 cells also secrete TNF-β, collaborating with macrophages and CD8+ T cells to attack tumor cells.

• Th2 (Type 2 Helper T Cells): Suppress immune responses, primarily through IL-4, IL-5, IL-9, and IL-10, which support eosinophils, mast cells, and B cells.

Additionally, T regulatory cells (Tregs) and Th3 cells function as potent immune suppressors, largely due to their secretion of TGF-β and other immunosuppressive cytokines. The balance between these helper T cell subsets is determined by antigen-presenting cells (APCs) and the instructional signals received upon antigen binding.

M1 vs. M2 Macrophages

• M1 Macrophages (Pro-inflammatory, Tumor-Suppressive):

  • Classically activated by IFN-γ

  • Produce pro-inflammatory cytokines

  • Engage in phagocytosis and antigen presentation

  • Stimulate CD8+ T cells and NK cells to attack tumor cells

• M2 Macrophages (Immunosuppressive, Tumor-Promoting):

  • Activated by IL-4, IL-10, or IL-13

  • Secrete immunosuppressive cytokines (e.g., IL-10, TGF-β, and PGE2)

  • Impair neoantigen presentation and suppress the anti-tumor function of T cells and NK cells

  • Incapable of directly lysing tumor cells

Although M1 and M2 macrophages can interconvert, the M1/M2 ratio is rarely reversed due to their inherent ability to reinforce their respective phenotypes. In general, Th1 cells and M1 macrophages collaborate to enhance immune activation, while Th2 cells and M2 macrophages jointly drive immune suppression, as illustrated in the figure below.

Fibroblasts and Tumor-Associated Fibroblasts (TAFs)

Fibroblasts are mesenchymal-derived cells that play essential roles in tissue repair and structural support. When exposed to damage signals, such as wounding, quiescent fibroblasts become activated to facilitate tissue healing. However, under pathological conditions, fibroblasts can transform into tumor-associated fibroblasts (TAFs), contributing to tumor progression.

How TAFs Drive Tumorigenesis

• Extracellular Matrix (ECM) Remodeling:

  • TAFs increase proliferation and enhance ECM production, promoting tumor growth.

• Cytokine Secretion:

  • TAFs secrete TGF-β, reinforcing a positive feedback loop that supports tumor growth and suppresses immune activation.

• Immune Exclusion:

  • TAFs drive desmoplastic stroma formation, leading to an immune-excluded phenotype, which prevents effective T cell infiltration into the tumor.

While normal fibroblasts can suppress tumorigenesis, TAFs actively promote it through ECM remodeling, cytokine secretion, and immune suppression.

The Complex Landscape of the Tumor Microenvironment

In summary, the tumor microenvironment is highly heterogeneous, comprising various immune cells, cytokines, and stromal components that interact dynamically. Immune cells related to adaptive immunity—such as CD4+ and CD8+ T cells, as well as M1 macrophages—are strongly associated with immune activation. In contrast, Tregs, myeloid-derived suppressor cells (MDSCs), and M2 macrophages contribute to immune suppression.

A comprehensive schematic from Brett Burkholder et al. (PMID: 24440852) provides an insightful overview of key immune cell–cytokine interactions in the tumor microenvironment.

Beyond TILs: Additional Factors Influencing the IO Cycle

While the immune response in the tumor microenvironment is crucial, several additional factors influence the immune-oncology (IO) cycle, including:

• Tumor Immunogenicity: The presence of neoantigens that trigger immune recognition

• Antigen-Presenting Cell (APC) Function: The ability of APCs to capture and present tumor-derived epitopes

• Immune Repertoire Diversity & Abundance: The breadth and clonality of T cells and B cells within the tumor environment

• Immune Checkpoint Inhibitor Expression: The regulation of immune checkpoints, such as PD-1/PD-L1 and CTLA-4, which modulate T cell responses

Given the complexity of these interactions, a broader discussion on the IO cycle and its regulation may be warranted in a future article.