Tumors are a heterogeneous group of cells from diverse organs, ranging from stem cells and endothelial cells, to a wide range of immune cells. The plethora of secretory signals from cancer cells have numerous effects that help promote tumor growth and progression, while also perturbing the immunologic surveillance of developing tumors. Cancerous cells express their own profile of cytokines and chemokines that facilitate inflammation, cell growth, and recruitment of new blood vessels, while also recruiting accessory cell populations for their survival and immunologic avoidance. Collectively, these local changes promote the developing tumor microenvironment (TME).
Interrogation of the tumor environment’s niche of cell signals, growth factors, and cytokines, as well as the TME recruitment of accessory cell populations and their cytokines, requires a global view of all these factors together. While a piecemeal approach may prove effective if the hypothesis is sufficiently narrow, a broad view of cancer will be needed for biomarker discovery and diagnostics moving forward. Multiplexed immunoassays remain the best and most complete means to study the proteomic changes within the TME, as they afford the most global view of protein changes from numerous and disparate cell populations. RayBiotech’s antibody array platforms therefore represent powerful tools for the identification of new cancer biomarkers, either from the local TME, or from the cancer cells themselves.
Th1 lymphocytes and M1 macrophages are the primary sources of pro-inflammatory cytokines that promote cancer immunosurveillance and cytotoxicity. Their interactions are mutually reinforcing: Secretion IFN-γ by Th1 cells results in the recruitment and maintenance of M1, while IL-12 produced by M1 macrophages recruits, activates and maintains Th1cells. Secretion of MIG/CXCL9 and IP-10/CXCL10 also promotes the recruitment of Th1 cells and CTLs and inhibits angiogenesis. IL-1α, IL-1β and IL-6 form an autocrine feedback loop by stimulation of myeloid differentiation primary response gene 88 (MyD88)-mediated activation of NF-κB signaling. TNF-α, also released by the activation of NF-κB signaling, which activates APC functions of DCs and the recruitment and cytotoxic activation ofM1 macrophages, effector CD4+ T cells, and CD8+ cells, as well as the recruitment of NK cells.
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.