4.Association of CD73 with other immune checkpoints
CD73 is expressed in various kinds of cancer, promoting tumor growth, metastasis, and drug tolerance in glioblastoma, melanoma, leukemia, colon, breast, ovarian, and bladder cancers[12, 15, 61].In human breast cancer cells, high expression of CD73 is related to low response and high resistance to anthracyclines[40, 42, 62].High level of CD73 is related to immunosuppression and tumor progression. Overexpression of CD73 in tumors not only leads to metastasis of tumor cells and anthracyclines resistance, but also leads to immune escape because of excess of adenosine production[63, 64].Therefore, inhibitors of CD73 are currently used in combination with existing cancer therapies for cancer immunotherapy, including anti-PD-1/PD-L1 and anti-CTLA-4 therapies[40, 42, 63].Although blocking CD73 alone does not result in a cure, inhibition of CD73 increases the antitumor effect of blocking immune checkpoint therapies, including anti-CTLA-4 and anti-PD-1 [15, 20, 63].Synergistic effects of combined CTLA-4 mAb with CD73 mAb and combined PD-1 mAb with CD73 mAb immunotherapy have been observed in both preclinical models of breast cancer and colon cancer[20, 41, 64].Currently, MEDI9447(AstrazenecaMedimmune), a human IgG1CD73 mAb[42], can selectively inhibit the activity of CD73ECN, and can cross-react with mouse and human CD73. MEDI9447 internalized the desetting of CD73 from the cell surface, thereby inhibiting the conversion of AMP to adenosine and removing inhibition of T cell proliferation that is mediated by AMP. In an immunoactive mouse tumor model, MEDI9447 reduces immunosuppressive effects and promotes antineoplastic function[41];BMS986179, a high affinity antibody, inhibits the activity of CD73 and mediates the internalization of CD73[15, 65];CPI-006 (also known as CPX006) acts mainly by inhibiting CD73 activity and/or inducing CD73 downregulation; IPH5301, which blocks AMP from degrading to the immunosuppressant adenosine. At present, these antibodies are undergoing early-stage clinical trials [10, 66]。