Cancer Genetics and Epigenetics 2017, Vol.5, No.7, 33-38
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are molecules that downregulate the immune response and prevent the over-activation of T-cells, thereby playing a
critical role in regulating peripheral tolerance.
2 Preclinical Advances in Tumor Treatment Mechanisms and Pharmacological Approaches in
Immune Checkpoint Therapy
Many patients involve gene mutations or genetic changes. These changes affect special T-cell populations by
inducing tolerance to tumors, cause a high expression of inhibitory receptors and related ligands and suppressing
T-cell activation which caused anti-tumor T-cells useless in tumor microenvironments. Thus, tumor cells are not
recognized by adaptive immunity or innate immunity systems, and can avoid attack from the host immune system
(Topalian et al., 2015; Parra et al., 2016). In an era when personalized medicine is strongly advocated in the field
of oncology, the sheer diversity of cellular mutations that occur in different cancers poses a significant challenge
to the personalization of cancer treatment. Here, the ‘common denominator’nature of immune checkpoint
blockades allow it to stand out amongst other conventional cancer treatments. At present, the most extensively
studied immune checkpoints are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, also known as CD152),
and programmed cell death protein 1 (PD-1, also known as CD279). These operate at different levels, and regulate
the immune response through different mechanisms (Duraiswamy et al., 2013). CTLA-4 is mainly expressed on
the surface of activated T-cells, and shares a high degree of commonality with CD28, another molecule that is
present on the surface of T-cells, and provides co-stimulatory signals. CTLA-4 and CD28 competitively bind to
the same ligands CD86 and CD80; CTLA-4 and CD28 have opposing effects on T-cell activation. The former
inhibits the initial stages of T-cell activation (Walker and Sansom, 2015). Studies on variety cell lines in mouse
tumor models have proven that treatment with CTLA-4 mAbs results in elevated cell line specificity. After
CTLA-4 mAb treatment, complete degeneration or stunted development of tumor tissue can be observed in
several types of tumor xenograft models, including ovarian cancer, bladder cancer, brain cancer and fibrosarcoma
(Fecci et al., 2007; Grauer et al., 2007; Grosso and Jure-Kunkel, 2013). The PD-1 immune modulation pathway is
similar to the CTLA-4 pathway in a number of ways, PD-1 does not exist on the surface of either quiescent
T-cells or memory T-cells, and is mainly expressed on activated T-cells, B-cells, and other cells of the immune
system. Cytoplasmic agents in PD-1 include Immunoreceptor tyrosine-based inhibitory motif (ITIM) and
immunoreceptor tyrosine-based switch motif (ITSM), which bind ligands (PD-L1 and PD-L2), then undergo
phosphorylation and recruit the intra-cellular signaling molecules Src homologous protein tyrosine phosphatase
(SHP-2), thereby triggering the dephosphorylation of the antigen receptor complex. This mechanism allows PD-1
to inhibit signals and control the effects of the T-cell immune response (Parry et al., 2005; Honda et al., 2014;
Topalian et al., 2015). PD-1 mAbs can prevent recognition between PD-1 and PD-L1, thus restoring the cytotoxic
effects of T-cells to a certain extent. Preclinical studies on treatment using PD-1 mAbs have led to important
breakthroughs in the field of oncology. Pembrolizumab, a PD-1 inhibitor, has been proven to decrease the
mortality of patients with melanoma, and has been used in the treatment of other cancer types, such as
non-small-cell lung carcinoma, renal cell carcinoma, head and neck cancers, bladder cancer, breast cancer, and
Hodgkin’s lymphoma (Kantoff et al., 2010; Hodi et al., 2010; Gangadhar and Salama, 2015; Li et al., 2016). The
targeted therapeutic application of PD-1 mAbs has revolutionized conventional treatments in oncology. Future
work will be focused on designing personalized strategies for combination therapy of immunesuppressant, to
strengthen antitumor immune responses and overcome the limitations of tumor resistance.
3 Preliminary Studies in Molecular Imaging of Immune Checkpoints
3.1 Non-invasive selection of patient populations likely to benefit from immune checkpoint therapy
With respect to PD-1/PD-L1 blockade therapy, the use of targeted PD-1 and PD-L1 blockers has achieved
significant success in treating patients with cancer that overexpress PD-L1. However, not all cancer cells express
PD-L1, and as a result, not all patients are suitable candidates for immune checkpoint blockade therapy. To better
realize the aim of personalized medicine, clinicians are experiencing an urgent need for a selection method to
accurately predict which patients stand to benefit from the administration of pharmacological immune checkpoint
blocker agents. Immunohistochemical (IHC) studies have shown that the expression of PD-1 proteins on CD8+
T-cells in infiltrated tumors can be used as a predictive marker for selection (Gros et al., 2015). However, the
