Cancer Biology III: Tumor Microenvironment

Tumor Microenvironment (TME)

• The TME is a complex and dynamic environment surrounding a tumor, comprising various cells, signaling molecules, and the extracellular matrix.
• It plays a critical role in tumor development, progression, metastasis, and response to therapy.

Key Components of the TME

• Cancer cells: primary malignant cells that drive tumor growth and progression.
• Stromal cells:
  • Fibroblasts: produce extracellular matrix components and secrete growth factors.
  • Endothelial cells: form blood vessels that supply nutrients and oxygen to the tumor.
  • Pericytes: support and stabilize blood vessels.
• Immune cells:
  • T cells: can attack cancer cells but often become suppressed or exhausted.
  • Macrophages: can be tumor-promoting (M2 type) or tumor-suppressing (M1 type).
  • Tumor-associated macrophages (TAMs): promote tumor growth and metastasis by creating an immunosuppressive environment.
  • Myeloid-Derived Suppressor Cells (MDSCs): suppress the immune response.
  • Dendritic cells: present antigens to T cells, initiating immune responses.
  • Natural Killer (NK) cells: attack and kill cancer cells.
• Blood vessels and angiogenesis:
  • Formation of new blood vessels to supply the growing tumor with nutrients and oxygen.
  • Facilitated by endothelial cells and pericytes, often driven by VEGF (vascular endothelial growth factor).
• Extracellular matrix (ECM):
  • Proteins like collagen, fibronectin, and proteoglycans.
  • Provides structural support and regulates signaling pathways.
  • Altered ECM can enhance tumor cell proliferation, migration, and invasion.
• Signaling molecules:
  • Cytokines, chemokines, growth factors (e.g., TGF-β, IL-6, IL-10, VEGF).
  • Mediate communication between cancer cells and TME components.
  • Support tumor growth, immune evasion, angiogenesis, and metastasis.

Association of TME in Cancer Development

• The presence of immune cells like CD4+ T helper 1, CD8+ T cells, natural killer cells, and M1 macrophages is correlated with immune control.
• The presence of immune cells like CD4+ T helper 2, CD4+ regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells forms a complex network that supports immune escape.

Immune Evasion Strategies Used by Tumor Cells

• Alteration of antigen presentation:
  • Cancer cells can downregulate expression of MHC molecules that present tumor antigens to T-cells.
  • Suppress tumor antigen presentation by professional APC, thereby avoiding recognition by T-cells.
• Recruitment of immunosuppressive cells:
  • Tumors create an immunosuppressive environment by recruitment and retention of suppressive Tregs and MDSCs.
• Secretion of immunosuppressive cytokines:
  • Secretion of immune-regulating or suppressive cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13) and mediators (prostaglandins, indoleamine 2,3-dioxygenase) by suppressive Tregs and MDSCs.
• Expression of immune checkpoint molecules:
  • Dysregulation of T-cell checkpoint pathways, including expression of PD-L1 by tumors, sends negative signals to tumor-specific T cells, causing T cell inactivation.

Interaction between Costimulatory and Immune Checkpoint Ligand-receptor

• Interaction between costimulatory molecules (e.g., CD28, CD80) and immune checkpoint ligand-receptor (e.g., PD-1, PD-L1) regulates T cell function and immune response.