Page 254 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 14 Cancer Immunotherapy 233

Tumors also can express other immune suppressive molecules suppression by MDSCs include suppression of T cells through
that work in modulating the tumor microenvironment. An exam- production of inducible nitric oxide species (iNOS), reactive oxy-
′
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gen species (ROS), arginase, and cysteine deprivation. MDSCs
ple would be CD73, an ecto-5 -nucleotidase that catalyzes the
VetBooks.ir breakdown of AMP to the adenosine. When expressed on tumors, can produce transforming growth factor-beta(TGF-β) and IL-10,
which stimulate Tregs and TAMs, and MDSC can cause down-
this creates a local microenvironment rich in adenosine, which is
immunosuppressive. Indoleamine deoxygenase is another highly regulation of the IL-12 production by TAMs, a cytokine involved
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immune suppressive molecule expressed locally by tumors and in T-cell activation. MDSCs cause NK cell anergy (lack of func-
tumor-infiltrating myeloid cells. 29,30 tion) also by this decreased IL-12 production and through mem-
Lastly, tumor cells are also capable of avoiding immune elimi- brane-bound TGF-β. 62,63 Thus given the ability of these cells to
nation by failing to be recognized by the immune system in the use multiple pathways to induce tumor immunosuppression, the
first place. For example, some tumor cells can down-modulate development of effective immunotherapies that can target these
major histocompatibility complex (MHC) surface expression to cells and either eliminate them or lead to their maturation, rather
escape recognition by T cells. MHC Class I expression can be lost than ones that target specific pathways of suppression, is critical
on tumor cells due to changes in protein synthesis, structure, or for that therapy’s success.
allelic loss. 31,32 Moreover, defects in antigen processing and pre-
sentation can occur that can also lead to decreased MHC expres- Induction of Regulatory T Cells by Tumors
sion. 31,32 A decrease in MHC class II expression is also observed Numbers of regulatory T cells (Tregs) are expanded in cancer
in certain human hematopoietic cancers, although it should be patients, in tumor tissues, tumor-draining lymph nodes, bone
noted that most tumors are normally MHC class II negative. 33,34 marrow, and blood. 64–66 These cells are phenotypically defined
Reduced expression of MHC class II has been recently correlated by surface expression of CD4 and CD25 but are most specifi-
with poor outcome in dogs with B cell lymphoma. Thus tumor cally identified by the intracellular transcription factor, forkhead
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cells themselves can actively and directly suppress antitumor T cell box P3 (FoxP3). 67,68 Other surface markers used to identify Tregs
responses through such mechanisms as decreased expression of include CTLA-4, GITR, Lag3, and folate receptor 4 (FR-4). 69–72
MHC molecules and increased expression of inhibitory molecules. Tregs are capable of directly suppressing tumor-specific CD4+
and CD8+ T cells and NK cells and are enriched in the tumor
Active Immune Suppression by Myeloid-Derived Suppres- microenvironment by conversion of CD4 T cells to Tregs by
sor Cells locally produced factors such as IL-6 and TGF-β. 73–76 Prolifera-
A population of cells in the tumor microenvironment that plays a tion of tumor-specific Tregs occurs after antigen recognition, or
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major role in tumor immunosuppression is myeloid-derived sup- recruitment of these cells via chemokine signaling (i.e., CCR5).
pressor cells (MDSCs). These cells consist of immature monocytes Recent work has also suggested a role for the chemokine CCL-1
and granulocytes released from the bone marrow into the blood in in specifically converting T cells to Tregs and inducing their sup-
response to sustained inflammation, including cancer. 36–44 Some- pressive nature. 78
times included in the functional description of this group of cells Many studies demonstrate that increased numbers of Treg
are tumor-associated macrophages (TAMs), which have the same cells are correlated with a poor prognosis. 64,79–81 In addition,
ability, and use similar mechanisms as MDSCs, to induce potent Tregs present in metastatic lymph nodes inhibit the ability of
tumor immunosuppression. 45,46 Numerous studies demonstrate tumor-infiltrating lymphocytes to mount an effective antitu-
increased numbers of MDSCs in humans with cancer 47–49 and in mor response. Work in the author’s laboratory demonstrated
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mouse cancer models. 40,50 Furthermore, it has been shown that that canine Treg cells can also be identified via the expression of
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the presence of these cells correlates with clinical disease stage and CD4 and foxp3. Moreover, they reported previously that can-
metastatic tumor burden in humans with solid tumors. MDSCs cer-bearing dogs had increased numbers of Tregs compared with
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are released from the bone marrow in response to cytokines healthy dogs and that this difference was greater in certain types of
released in inflammation, including granulocyte-macrophage canine cancer. 65,83 Therefore current therapies aimed at depleting
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colony stimulating factor (GM-CSF) and interleukin-3 (IL-3). Treg cells in humans could be applied to veterinary medicine. In
MDSCs can be recruited to the tumor microenvironment by mul- particular, many studies have shown that the use of cyclophos-
tiple chemokines, many of which are produced by the tumor dur- phamide or anti-Treg-specific antibodies decreases the numbers
ing times of hypoxia and are regulated by hypoxia-inducible factor of Tregs present in tumors and in circulation of tumor-bearing
1α (HIF-1α) production. 45,52–60 Once within the tumor micro- patients. 84–88 In addition, it was shown that the tyrosine kinase
environment (TME), MDSCs differentiate into macrophages or inhibitor drug toceranib (Palladia) can deplete canine Tregs both
neutrophils and actively suppress the local antitumor immune in vitro and in vivo.
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responses and promote tumor invasion and metastasis via the
production of matrix metalloproteinases (MMPs). 43,61 Moreover, Impaired Dendritic Cell Activation and Function
TAMs stimulate tumor angiogenesis and promote metastasis. Of Another important mechanism of tumor suppression is through
45
note, there is still no clear consensus on how to identify MDSC impairment of the potent antigen-presenting cells, dendritic cells
in humans, mice, or dogs, thus making it more difficult to clearly (DCs). Numerous studies have denoted that overall numbers of
define the role that MDSCs play in cancer. DCs are decreased in various human cancers studied, including
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The ability of MDSCs to suppress the antitumor response is head and neck squamous cell carcinoma (HNSCC), breast and
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the subject of many recent studies. 42,62,63 Numerous mechanisms prostate cancer, and malignant glioma. A recent study showed
of suppression have been reported and MDSCs have the ability that indoleamine 1 (IDO1), expression in the tumor microenvi-
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to suppress not only T cells, but also natural killer (NK) cells and ronment led to increased DC apoptosis. The aforementioned
DCs. They are also able to potentiate T regulatory cells (Tregs, tumor studies demonstrated fewer circulating myeloid DCs with
discussed in the text that follows) and differentiate into TAMs in a concurrent increase in immature DCs (iDCs) with reduced
the tumor (see Fig. 14.1). Current known mechanisms of immune ability to present antigen and stimulate T cells; thus they induce