Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of various immune checkpoints. Immune checkpoints refer to plenty of inhibitory pathways hardwired into the immune system that are critical for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. Preliminary clinical data indicates that blockers of additional immune-checkpoint proteins allow broad and diverse opportunities to enhance antitumor immunity with the potential to produce durable clinical responses. Creative Biolabs, who is focused on animal model and antibody discovery, is proud to offer you the humanized CD73 immune checkpoint knock-in mice and professional technical support.
CD73 Immune Checkpoint Pathway
CD73 (cluster of differentiation 73), also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase, is an enzyme that commonly serves to convert AMP to adenosine. CD73 consists of a dimer of 2 identical 70-kD subunits bound by a glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. CD73 is a membrane-bound extracellular enzyme which is found in a variety of tissues, including colon, brain, kidney, liver, lung, and heart; on leukocytes derived from peripheral blood, spleen, lymph nodes, thymus, and bone marrow; as well as on endothelium. What's more, CD73 is always overexpressed in several cancer types. The expression of CD37 has been associated with poor prognosis in melanoma, colorectal, gastric, triple negative breast cancer, and to a pro-metastatic phenotype in prostate cancer.
CD73 is active during the last step of the degradation pathway, where it is the enzyme that actually degrades AMP into adenosine, and thus plays a vital role in promoting immunosuppression through the pathway degrading adenosine triphosphate (ATP) into adenosine. ATP accelerates immune cell-mediated killing of tumor cells within the tumor microenvironment. On the contrary, adenosine accumulation leads to immune suppression, dysregulation of immune cell infiltrates and stimulates angiogenesis contributing to tumor spread.
Fig.1. The CD39/CD73 axis in neoplastic development and progression. (Antonioli, et al., 2013)
Regulation of Immunity by CD73 in Cancer
Within the tumor microenvironment, tumor and immune cells closely interact to generate an immuno-suppressive environment by releasing immunomodulatory factors, which supports tumor growth. Several studies have demonstrated the crucial role of CD73 in generating this immunosuppressed environment, characterized by increased adenosine levels, which promotes the development and progression of tumor. The CD39/CD73 complex participates in the process of tumor immunoescape, by inhibiting the activation, clonal expansion, and homing of tumor-specific T cells (particularly the T helper and cytotoxic T cells), impairing tumor cell killing by cytolytic effector T lymphocytes, dictating, via pericellular generation of adenosine, a substantial component of the suppressive capabilities of Tregs and Th17 cells, and enhancing the conversion of type 1 macrophages into tumor-promoting type 2 macrophages.
Development of Humanized CD73 Immune Checkpoint Knock-In Mice
Previous studies have shown that CD73-blockade promotes anti-tumor immunity by reducing adenosine accumulation. Besides, data on mouse tumor models indicate that anti-CD73 monoclonal antibodies stimulate anti-tumor immunity and reduce tumor metastasis and could enhance the efficacy of treatment with anti-PD1 or anti-CTLA4 antibodies. Furthermore, it is becoming increasingly appreciated that altering the CD39/CD73 pathway can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders. Accumulative evidence suggests that interactions between tumor cells and their microenvironment are essential for tumorigenesis. Scientists in Creative Biolabs spare no efforts developing a variety of well-characterized Magic™ “humanized” animal models, which can provide you with humanized immune checkpoint knock-in mouse models including humanized CD73 knock-in mouse. Please feel free to contact us for more detailed information.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
For Research Use Only.
