Tumor microenvironment (TM) refers to the cellular environment surrounding a tumor, which includes blood vessels, normal cells and molecules. The interaction between a tumor and its microenvironment results in different physiological processes providing both beneficial and adverse consequences for tumorigenesis (Quail & Joyce, 2013).

Gene expression is altered in tumor cells to secrete molecules such as cytokines, growth factors, and cellular components, for instance, exosomes to recruit stroma and vascular cells (Quail & Joyce, 2013; Mittal et al., 2014). Regardless of different tumor types and their tissue of origin there are some general hallmarks that govern tumorigenesis. Various immune effector cells can also be found in tumor microenvironment, yet their anti-tumor functions are downregulated due to tumor-derived signals such as cytokines (Whiteside, 2008).

Figure 1: Tumor Microenvironment
In the tumor microenvironment the levels of VEGF (vascular endothelial growth factor) are increased, while the extracellular pH as well as the oxygen concentration decrease, which creates an acidic and hypoxic environment.

Hypoxia is defined as the reduction or lack of oxygen in organs, tissues or cells (Yotnda et al., 2011). Hypoxia (Fig. 1) is a constantly evolving participant in overall tumor growth (Patel & Sant, 2016; Kim et al., 2009) and remains the predominant regulator of angiogenesis in the tumor microenvironment (Mittal et al., 2014). The actual physiological levels of oxygen level in healthy tissues ranges from 3-6 % (Tian & Bae, 2012), while that of tumors are approximately 1 % (McKeown, 2014), which can be an important factor to distinguish healthy tissues and tumors.

Tumor angiogenesis is normally induced by a tumor to generate its dedicated blood supply for oxygen and other nutrients by secretion of various growth factors, including vascular endothelial growth factor (VEGF). VEGF (Fig. 1) promotes growth of blood vessels and is regarded as constituent element of the tumor microenvironment (Mittal et al., 2014). The concentration of VEGF in tumor fluids of cancer patient ranges depending on tumor types from 1.7 pM to 320 pM (Finley & Popel, 2013).

In addition, acidic extracellular pH (Fig. 1) is a major feature of tumor tissue due to lactate secretion from anaerobic glycolysis and CO₂ from the pentose phosphate pathway (Kato et al., 2013). Studies on different tumor nodules in human patient reveal an average extracellular pH of 7.0, in contrast to the physiological pH of 7.4 (Tian & Bae, 2012).

Those factors that determine the nature of tumor are considered by most therapeutic approaches to develop targeted therapies. Hypoxia, low pH and VEGF are three common characteristics of the tumor microenvironment. Therefore we chose these conditions to control the expression of chimeric antigen receptor (CAR) in T cells by an AND gate.