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)