Page 255 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

234 PART III Therapeutic Modalities for the Cancer Patient

T-cell tolerance rather than activate T cells. 91–93 The DCs present immunosuppressive cytokines. 106 A few key immunosuppres-
in the tumor tend to be immature and dysfunctional. Studies of sive cytokines produced by tumor cells are IL-10, VEGF, and
106,107
TGF-β.
These cytokines act to suppress antitumor T cell
DCs in numerous human cancers demonstrate minimal activa-
VetBooks.ir tion, decreased ability to stimulate in an alloreactive fashion, and responses and inhibit DC function. IL-10 promotes Treg pro-
A simi-
and, in an autocrine and/or paracrine
90,91,94–99
decreased expression of costimulatory molecules.
108
duction and function
lar study done in dogs with canine transmissible venereal tumors fashion, may potentially affect tumor cell proliferation and sur-
(CTVTs) showed that the tumor environment caused downregula- vival. 109 In human cancer patients, increased levels of serum
tion of DC surface markers of activation and MHC, and decreased IL-10 are observed in patients with either pancreatic carcinoma
endocytic capabilities and decreased allogenic mixed lymphocyte or non-Hodgkin lymphoma (NHL). 110,111 In addition, elevated
reaction (MLR) responses. Possible mechanisms causing the DC levels of IL-10 in diffuse large B-cell lymphoma of humans cor-
56
dysfunction include the overexpression of the protein S100A9, 100 relate with a poor prognosis. 112 TGF-β acts similarly to IL-10 in
accumulation of triglycerides in the DCs which leads to decreased that it is a potent immunosuppressive cytokine that can potenti-
capacity to present antigen, 101 and downregulation of toll-like ate Treg proliferation and function. 74,113–115 It can also enhance
receptor (TLR)-9 expression. 102 Moreover, factors such as IL-10 tumor progression; carcinomas can produce excess TGF-β,
and vascular endothelial growth factor (VEGF) can negatively which in turn increases the epithelial-to-mesenchymal transi-
affect DC function and maturation. 103,104 Lastly, some DCs in tion, tumor invasion, and metastasis and inhibits tumor-specific
the tumor are considered to be regulatory based on low expres- CD8+ T cells. 115 Moreover, tumor-produced tumor necrosis
sion of surface markers MHC II, CD86, and CD11c with high factor-alpha (TNF-α) leads to promotion of tumor cell survival
expression of costimulatory molecules CD80, CD40, CD106, via induction of antiapoptotic proteins. 116 Finally, TNF-α has
and CD11b. These cells secrete regulatory factors such as IL-10 been shown to promote tumor angiogenesis and metastasis and
and nitric oxide (NO) and inhibit proliferation of naïve CD4+ T hamper cytotoxic T-cell and macrophage responses. 117
cells to antigen presented by mature, functional DCs. 105 Overall, One study in veterinary medicine examined a lymph node
the microenvironment of the tumor leads to attraction of imma- of a dog with metastatic melanoma. This study revealed an
ture and regulatory DCs that, due to their decreased activation overexpression of IL-10 and TGF-β concurrent with a lack of
and function, can potently inhibit the development of antitumor expression of IL-2, IL-4, or interferon-gamma (IFN-γ) cytokines
T cell responses even when copious amounts of antigen are present. typically associated with antitumor immunity, thus demonstrat-
ing that tumor immunosuppression occurs in veterinary patients
Production of Immunosuppressive Cytokines as well. 118 For a review of cytokines relevant to tumor immuno-
In addition to the suppressive milieu established by tumor-infil- therapy, see Table 14.1.
trating cells, tumor cells themselves are capable of producing

TABLE 14.1 Biological Activities of Key Cytokines Relevant to Tumor Immunotherapy
Cytokine Major Activity
IL-2 Growth factor for T cells, including regulatory T cells; induces proliferation and differentiation of T cells to effector T cells; enhances CTL and NK cell
cytotoxicity, production of LAK cells, induces B-cell proliferation. Approved for use clinically by the FDA.
IL-3 Multicolony-stimulating factor, promotes production/differentiation and proliferation of macrophages, monocytes, granulocytes, and dendritic cells;
secreted by activated T cells and supports growth and differentiation of T cells.
IL-4 Key Th2 cytokine; induces differentiation of naïve CD4 T cells toward Th2 phenotype, inhibits macrophage activation, induces B cell growth and
differentiation, stimulates isotype switching and IgG and IgE production. Up-regulates MHC Class II production.
IL-6 Supports B-cell proliferation and differentiation to plasma cells; proinflammatory, antiapoptotic cytokine that may contribute to tumor development
associated with chronic inflammation. Causes upregulation of PD-1 on monocytes that are triggered to produce IL-10 after ligation of this recep-
tor.
IL-8 Chemotactic/activation factor for neutrophils and T cells; induces matrix metalloproteinase-2 activity; plays a role in inflammation and tumor metas-
tasis.
IL-10 Immunosuppressive cytokine produced by activated DCs, macrophages, and T cells; induces regulatory T cell function; also overexpressed by some
tumors and tumor-associated leukocytes.
IL-11 Stimulates proliferation of hematopoietic stem cells; induces megakaryocyte maturation resulting in increased platelet production.

IL-12 Key Th1 cytokine produced by DCs, macrophages; stimulates synthesis of IFN-γ and TNF-α by T cells and NKs, thus decreasing angiogenesis,
enhances cytotoxicity of CTLs and NK cells, stimulates differentiation of naïve CD4+ T cells to T cells with the Th1 phenotype.
IL-13 Th2 promoting cytokine, produced by NKT cells; inhibits inflammatory cytokine production by macrophages; possible inhibitory role in tumor immu-
nosurveillance.
IL-15 T cell growth factor; supports survival of memory CD8+ T cells; promotes NK cell activation and survival and triggers cytotoxic activity.
IL-17 Induces proinflammatory response. Role in cancer is currently controversial—depending on context, may either promote or inhibit tumor growth.
IL-19 Promotes T-cell differentiation toward the Th2 phenotype.
IL-21 Member of IL-2 cytokine family; enhances cytotoxicity and proliferation of CTL and NK cells.