**4.1.2 T Cells**

T cells orient their cytoskeleton and migrate towards sites of inflammation, such as those present in a tumour microenvironment (TME), in a PKC-dependent manner as a direct result of CD44 crosslinking by HA (Fanning *et al*., 2005). In BCA, CD8+ T cells are most predominant in advanced cancer stages where their presence in proliferating tumours is a good prognostic indicator. T cells are able to participate in either a Th1 or Th2 polarized immune response and, when polarized to a Th1 response, they express and secrete IFNγ, TGFβ, TNFα, IL-2, resulting in cytotoxic cooperation (T cells and M1). Th2 polarized CD4+ T cells secrete IL-4,5,6,10,13 which leads to an increase in B cell mediated immunity (DeNardo and Coussens, 2007). Because of the anti-tumour effects of T cells, the activation of cytotoxic T cells against HA receptors as immunotherapy in leukemias is currently undergoing clinical trials and will be discussed later in this chapter. On the other hand, the presence of CD4+ T cells correlates with disease progression and metastasis; however, it has been shown by different groups that CD4+ T cells are crucial for mounting an immune response against cancer. For example, tumour growth of EL4 lymphoma cells inoculated into mice is inhibited by the presence of dendritic cells primed against RHAMM protein. This interaction, however, is dependent on CD4+ T cells, as the effect of DC killing of the tumour is significantly reduced with a reduced CD4+ T cell population (Fukui *et al*., 2006). Furthermore, Rakhra *et al.* (2010) showed that in ALL and B-cell leukemia, CD4+ cells were necessary for sustained tumour regression. In mouse models, inhibition of MYC or BCR-ABL rescues tumours from oncogene addiction; however, tumours regress in the presence of TSP-1 induced CD4+ T cells, and knockdown of TSP-1 impairs this ability (Rakhra *et al*., 2010).

Regulatory T cells (Treg; CD4+/CD25+/FOXP3+) play controversial roles in tumour progression and can have both anti- and pro-tumourigenic effects, depending on the chemokines or cytokines produced and the type of solid tumour. Treg cells may be activated in an immunosuppressive manner, preventing cytotoxic immune responses, and allowing the tumours to evade immune attack. For example, in CLL, a large Treg population dampens specific CD8+ T cell responses against tumour associated antigens (Giannopoulos *et al*., 2010). The same may be true for solid tumours. When coordinated, however, with a high T cell density, they may indicate good prognosis and inhibition of metastasis (Camus *et al*., 2009, Carreras *et al*., 2006).
