Cancer

Th2 lymphocytes, M2 macrophages and MDSCs mutually reinforce the proliferation and phenotypes of one another, as well as maintaining tumor-promoting inflammation and angiogenesis. These cells, along with T regulatory lymphocytes (TREGs) suppress the activity and proliferation of tumor-suppressing cells, including Th1, M1 and cytotoxic T cells and NK cells. It should be noted that M1 &M2 macrophages can interconvert, but these phenotypes are stable as the M1 and M2 expression profiles reinforce their own macrophage phenotypes, while suppressing the other. Similarly, Th1 & Th2 lymphocytes, as well as TREG & Th17 lymphocytes tend to self-reinforce their own activation profiles and inhibit the other.

Normal cells may become nascent tumors by evading tumor suppression after carcinogenic mutation and/or apoptosis that would normally result from gross chromosomal changes. Pro-inflammatory and pro-angiogenic factors can help to establish blood supply for the growing nascent tumor. Activation of the adaptive or native immune response can eliminate the nascent tumor, the tumor may remain in equilibrium as an occult tumor, or the tumor may escape immunosurveillance to create a viable tumor-supportive microenvironment. Innate and adaptive immune responses may still work to eliminate the tumor via immunosurveillance. Tumors may also metastasize to move to another location; this may be an additional mechanism of avoiding immunosurveillance by evacuation of the “hostile” TME. Green color denotes processes potentially leading to tumor eradication, while red color means promoting tumor escape and progression.

In the TME, a positive feedback loop of cytokine signals that proceeds as follows: First, TGF-β, COX2, PGE2, Th2- associated inflammatory factors and proangiogenic proteins are secreted by cancer cells, CAFs and other cell types in the nascent tumor recruit Th2 lymphocytes, M2 macrophages (TAMs) andN2 neutrophils (TANs). Then, Th2 lymphocytes, TAMs and TANs secrete additional inflammatory and proangiogenic proteins that suppress maturation of DCs and proliferation and activation of cytotoxic cells. As a result, antigen presentation and cytotoxic activities plummet, practically eliminating immunosurveillance in the tumor milieu. Additionally, B cells proliferate, but are not activated, turning them into tumor-promoting BREGs. M2macrophages recruit MDSCs to the TME, further reinforcing the positive feedback loop of Th2, M2, and N2 proliferation and activation, resulting in substantial increases in tumor-promoting inflammation and concomitant angiogenesis.