A glance into tumor microenvironment

Ghost came across this interesting figure on Cell Science and would like to take this opportunity to talk about tumor microenvironment.

A route towards tumorigenesis

Tumor microenvironment is dynamic battlefield between tumor and immune system. This long-lasting battle, widely known as tumorigenesis, usually takes three main stages to achieve tumorigenesis.

  • Immunosurveillance: The phase when immune system overwhelms tumor cells. multiple effector cells, such as T-cells, NK and certain types of macrophage are recruited and activated to fulfill their role of killing tumor cells

  • Equilibrium: A proportion of tumor cells can't stand the immune attack and die while a small proportion of them continue evolving through genetic changes and keep fighting the immune system.

  • Escape: At some point, the survival tumor cells prevail. They reshape themselves genetically or turn the surroundings into an immune suppressive environment to protect them from immune attack while they rapidly proliferate.

Long story short, the tumorigenesis process turns the tumor microenvironment from immune supporting into immune suppressive.

TIL composition and localization

In an ideal immuno-oncology cycle, certain types of immune cells get activated and recruited to tumor tissue collaborating with each other to kill tumor cells. However, through expression or epigenetic changes, tumor cells are often able to recruit different set of immune cells and create the immune suppressive environment. Such changes are usually reflected by either TIL composition change or localization change.

Regarding TIL composition, aside from apparent immune effector like CD4, CD8, here are some components worth mentioning:

Th1 vs Th2

Type 1 T helper (Th1) promotes while type 2 T helper (Th2) suppresses immune activity. Both of them regulates themselves in a positive feedback fashion.

Th1 secretes IFN-γ which promotes the production of IL-12 by DC and macrophages and vice versa. Besides, it secretes TNF-β as well and work with macrophage and CD8 to attack tumor cell

Th2 is promoted by IL-4. they secrete IL-4, IL-5, IL-9 and IL-10 and work with eosinophils, mast cells and B cells

Besides, Treg and Th3 are considered as immune suppressor largely due to their production of TGF-β and other immune suppressing chemokines. Schematic below briefly describes their interaction. All these types of helper T cells derived from immature T cells play almost opposite role in terms of immune response. Which direction do immune T cells go largely depends on the instruction they received when bind with APC that carries antigen.

M1 vs M2

Macrophage type 1 (M1) are classically activated, typically by IFN-γ, produce proinflammatory cytokines, phagocytize microbes, and initiate an immune response

Macrophage type 2 (M2), commonly known as TAM, are activated by IL-4, IL-10, or IL-13. They produce immunosuppressive cytokines like IL-10, TGF-β and PGE2. Ability of M2 to present neoantigen is decreased as well as stimulation of the anti-tumour functions of T cells and NK cells. Also M2 is not able to lyse tumour cells.

Note that although M1 and M2 can interconvert, the M1 / M2 ratio is rarely reverse due to their ability of reinforcing their own phenotype.

In general, Th1 and M1 collaborate to stimulate immune activity while Th2 and M2 together suppress immune activity as depicted in figure below.

Fibroblast and TAF

Fibroblasts (TAF) are an abundant mesenchyme-derived cell type. Quiescent fibroblasts differentially respond to damage, such as wounding, and become activated to support repair. TAF can rise through unique damage signal to which fibroblasts are exposed or by their origin. For example, secreting TGF-β in the positive feedback way. However, TAF can rise from other sources, such as endothelial cells, adipocyte, epithelial cell

Although normal fibroblast suppresses tumor, TAF promotes tumorigenesis by remodeling ECM through increasing proliferation, enhanced EM production and unique cytokine secretion. Besides, TAFs secrets TGF-β which supports the establishment of the desmoplastic stroma causing immune-excluded phenotype.

In general, those immune cells related to adaptive immunity, such as CD4, CD8 and M1 are significantly associated with immune activation. On the opposite, Treg, MDSC and M2 are mostly immune suppressive. Here is an informative schematic from Brett Burkholder's paper (PMID: 24440852) describing the major immune cells / cytokine interaction in tumor microenvironment.

After all, the tumor environment is highly heterogeneous with all kinds of cell types / cytokine interacting with each other. The components mentioned above are so far widely studied for their role on modulating tumor environment. Besides, the entire immune-oncology (IO) cycle as a complex biological process goes far more beyond what have been discussed above. Much more factors may affect IO cycle including:

  • Tumor immunogenicity (neoantigen)

  • The ability of APC to capture and present epitope

  • The diversity and abundance of immune repertoire

  • The expression of immune checkpoint inhibitors

The discussion of these additional factors on IO cycle level maybe worth a separate talk in the future.