Adaptive immune response to tumour cells
Cytotoxic T lymphocytes (CTLs) are the primary mechanism of tumour cell killing in adaptive immune response, which in many cases, requires the participation of APCs to present the relevant tumour antigen to the CTLs. MHC-I and-II molecules must be present to stimulate the production of CTLs. Typically, MHC-I APCs such as dendritic cells (DC), present antigen (tumour-derived peptides) to CD8+ T cells in the context of co-stimulation through CD80, CD70, and 4-1BB, as well as through dendritic cells (DC)-derived cytokines such as IL-12, type 1 interferon, and IL-15. CD8+ CTLs have been demonstrated in numerous different types of solid tumours in vivo and have been shown to cause tumour cell destruction in vitro. CD4+ T helper cells release cytokines, leading to the anti-tumour immune reaction. The Th 1- polarized CD4+ T cells secrete IL-2. TNF-α, and IFN-λ, which promote the development of CD8+ CTLs and the activation of macrophage cytotoxic activity. In addition, they can upregulate antigen processing and the expression of MHC-I and-II molecules in professional APCs such as macrophages and DCs. In contrast, Th2 polarized CD4+ T cells release cytokines IL-4,-5,-6,-10 and -13, resulting in T-cell-mediated cytotoxicity, enhance humoral immunity, and regulate the tumor-promoting activities of macrophages. In addition to the effector mechanism mediated by CTLs, the host immune system can generate specific antibodies against cancer antigens, which exert cytotoxic effect against the antigen-bearing tumour cells. Rather than recognizing only protein-derived antigens by T cell antigen receptors, antibodies can bind to multiple types of tumour antigens including polysaccharides, lipids and proteins. This enhances anti-tumour ability by broadening the number of tumour antigens that can be exploited for cytotoxic reactions. Mechanisms of antibodies mediated tumour cytotoxicity include antibody-dependent cell-mediated cytotoxicity (Type VI hypersensitivity reaction) and complement-mediated cytotoxicity [33]. Cancer vaccines against the tumour associated antigens may stimulate the immune system so that it recognizes the cancer cells as foreign and attacks the cells. Cancer vaccines are made with cells from the patient’s own tumour, modified in the laboratory and then returned to stop, destroy or delay the growth of cancer [34, 35]. Combination of whole cell vaccine GVAX and mesothelin-secreting vaccine CRS-207 demonstrated an overall survival benefit in metastatic refractory pancreatic cancer patients [36]. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins. The anti-Gal ligand is a carbohydrate antigen called α-gal epitopes which is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). As cancer cells or pancreatic ductal adenocarcinoma (PDAC) tumour lysates are processed to express α-gal epitopes vaccination with these components results in in- vivo opsonisation by anti-Gal IgG in PDAC patients [37]. The Fc portion of the vaccine- bound anti-Gal interacts with Fc receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumour membranes to draining lymph nodes, and processing and presentation of tumour-associated antigens (TAAs). It also elicited strong antibody production against multiple TAAs contained in pancreatic ductal adenocarcinoma cells and induce activation of multiple tumour-specific T cell [37, 38]. Murine dendritic cell, loaded with pancreatic tumour-specific glycoepitope C-ter-J28+, induces efficient anticancer adaptive immunity and represents a potential adjuvant therapy for patients afflicted with PDAC [39].