Adenosinergic Axis and Immune Checkpoint Combination Therapy in Tumor:A New Perspective for Immunotherapy Strategy
Zhaoyun Liu1*, Xiaohan Liu1*, Hongli Shen1, Xintong Xu1, Xianghong Zhao1, Rong Fu1
Addresses:1 Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin 300052, PR China.
*These authors contributed equally to this manuscript.
Corresponding author: Rong Fu
Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin 300052, PR China. Telephone: (086) 02260817181. Fax number: (086) 02260817181. E-mail:furong8369@tmu.edu.cn
Abstract :Tumor cells escape anti-tumor immune response in various ways, including functionally shaping the microenvironment through secretion of various chemokines, cytokines, etc. Adenosine is a powerful immunosuppressive metabolite, which is frequently found to be elevated in the extracellular tumor microenvironment (TME). Thus, it has been proposed as a novel antitumor immunoassay to target adenosine generating enzymes such as CD39, CD73, and adenosine receptors in recent years. The discovery of the immune checkpoint such as programmed cell death 1(PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), have also greatly changed the treatment methods and ideas of malignant tumors. The idea of malignant tumor immunotherapy has been developed from point-to-point therapy targeting immune checkpoint to combine different points of different pathway to create a kind of therapy based on macroscopic immune regulatory system network. This article reviews the theoretical basis of adenosine energy axis and immune checkpoint combined therapy for malignant tumors and the latest advances in malignant tumors.
Keywords:adenosine, CD39, CD73, A2AR, PD-1, CTAL-4
Adenosinergic Axis and Tumor Immunology
Adenosine, an important regulator of metabolism as well as a key immune checkpoint regulator,which associated with tumors evading the host immune system[1-3].Extracellular adenosine (eADO) is considered as an inhibitor of immune function. One of the major mechanisms of tumor immune evasion is the production of high eADO levels via overexpression of ectonucleotidases[4-6]. An effective immune suppressive microenvironment is sustaind when ADO functions synergistically or in combination with other immunosuppressive mechanisms[7]. In 2006, high extracellular adenosine levels in tumors were discovered to play a key role in evading anti-tumor immune responses [8],the environment that is rich of adenosine in tumor may induce incompetent T cells [1, 9-11].Adenosine pathway is currently considered as an important pathway for the effectiveness of immunotherapy and has become an important target for cancer therapy [1, 12].Endogenous ATP (eATP) can be released in large quantities through cell necrosis, apoptosis and mechanical damage [13],and can also be actively secreted by tumour cells, immunocytes and other histocytes in the TME, triggered by various cell damage factors such as hypoxia, chronic inflammation, cytotoxic drugs, etc. [2].The main source of eADO is from continuous degradation of eATP, which involves many different extracellular enzymes, including NTPDase1/CD39 and CD73[2, 12, 13]. CD39 is found highly expressed in the tumor endothelium of TME and on most immunocytes (including macrophages, myeloid cells and FOXP3+ regulatory T cells (Treg), etc.) surface[3]. CD39 can stabilize FOXP3+Tregs and contribute to its immunosuppressive function [14]; furthermore, CD39 promotes type I Tregs differentiation, produces IL-10, and restricts the activation of NLRP3 inflammatory bodies in dendritic cells (DCs) [2, 12, 13]. CD73 can be found in different kinds of tissues, which includes the colon, liver, kidney, brain, lungs, and heart; leukocytes and endothelial cells of peripheral blood, lymph nodes, spleen and bone marrow[3]. Evidence suggests that CD73 expression and function are elevated in the presence of hypoxia and inflammatory mediators (TGF- B, IFNs, TNF-α, IL-1B and PGE2, etc.), and the expression of CD73 is also increased in several tumor tissues, suggesting that CD73 is involved in tumor genesis and development [2, 12, 13, 15], eATP is decomposed into eADO by the sequence of CD39 and CD73, which binds to adenosine receptors on cell membrane surface [2, 12, 13]. Among several known adenosine receptors, adenosine receptor A2a (A2aR) is the predominant subtype that is mainly expressed in most immunocytes [16]. A2aR stimulation usually provides immunosuppressive signals that inhibit T cell proliferation, cytotoxicity, production of cytokine, NK cell cytotoxicity, production of NKT cell cytokine, upregulation of CD40L, macrophage/DC antigen presentation, etc. [1, 15].(Figure1)