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].