CCR5 and CXCR4 Antagonists in Carcinomas: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Wilfredo Alejandro González-Arriagada.

The interaction between malignant cells and the tumor microenvironment is critical for tumor progression, and the chemokine ligand/receptor axes play a crucial role in this process. The CXCR4/CXCL12 and CCR5/CCL5 axes, both related to HIV, have been associated with the early (epithelial–mesenchymal transition and invasion) and late events (migration and metastasis) of cancer progression. In addition, these axes can also modulate the immune response against tumors. Thus, antagonists against the receptors of these axes have been proposed in cancer therapy.

  • cancer therapy
  • immunotherapy
  • chemokines
  • oncology

1. Introduction

Cancer involves multiple events, such as uncontrolled proliferation and DNA repair failures, that trigger genetic instability, invasion, migration, angiogenesis, and metastasis. These later events depend on the interactions between malignant cells and many cells belonging to the tumor microenvironment, leading to tumor progression [1]. These processes require the activation or inhibition of different cell signaling pathways mediated by cell surface receptors and their ligands for which the chemokine ligand/receptor axes play key roles [2]. According to their chemical structure, chemokines comprise four subtypes of cytokines (C, CC, CXC, and CX3C) that act as the ligand on one or more receptors. On the other hand, chemokine receptors CR, CCR, CXCR, and CX3CR are G protein-coupled receptors activated for one or more subtypes of chemokines [3].
In cancer, and other diseases, a chemokine receptor may activate a proinflammatory or anti-inflammatory pathway, a duality exploited by neoplastic cells to improve the capacity to (i) evade the immune system, (ii) degrade the extracellular matrix, and (iii) invade the neural or vascular compartment producing metastasis [3,4][3][4]. In this sense, the bgreat interest is the role of CXCR4/CXCL12 and CCR5/CCL5 axes in the pathogenesis of epithelial malignancies, including lung [5], gastric [6], pancreatic [7], colorectal [8], breast [9], ovarian [10], prostatic [4], hepatocellular [11], and head and neck carcinomas [12[12][13],13], as well as adenocarcinomas [14] and non-epithelial cancers such as melanoma [15], multiple myeloma [16], and lymphomas [17].
Preclinical investigations (in vitro and in vivo) have proved the efficacy of HIV-related chemokine receptor (HIVrCR) antagonists for cancer treatment. Chemokine receptor antagonist (CRA) drugs such as maraviroc (CCR5 antagonist) or plerixafor (CXCR4 antagonist) have shown a role in the suppression of cancer cell proliferation, migration, and metastasis [18,19][18][19]. Thus, the CRA-promoted blockade of these axes arises as an alternative or complementary therapy to improve outcomes in tumors resistant to radiotherapy and chemotherapy in carcinomas [11,20,21,22,23,24,25][11][20][21][22][23][24][25].

2. CXCR4/CXCL12 Axis

In normal tissues, this axis is important in developmental processes, hematopoiesis, and inflammation [31][26] and is expressed in leukocytes, stromal fibroblasts, and endothelial cells [32][27]. CXC chemokine receptor 4 (CXCR4) is a G-protein-coupled receptor highly expressed in different human carcinomas [4[4][6][7][8][11][13][28],6,7,8,11,13,29], at all stages of the epithelial–mesenchymal transition, invasion, or metastasis [33][29], and has been related to a poor prognosis. Leukocytes and CAFs are sources of CXCL12 [34][30], a chemokine that binds to CXCR4, forming the CXCL12/CXCR4 axis. This axis has a role in different tumor pathways involved in processes such as the epithelial–mesenchymal transition, cell migration, and metastasis, including drug resistance [35,36,37][31][32][33]. Small molecules, such as AMD3100 (plerixafor), WZ811, LFC131, AMD070, LY2510924, X4-136, BPRCX807, and others [19,38[19][34][35][36][37][38][39][40][41][42][43][44][45][46],39,40,41,42,43,44,45,46,47,48,49,50], have been reported to inhibit CXCR4, individually or in association with other drugs or therapies (doxorubicin, cisplatin, radiation, and others) [19,40[19][36][37][44][45][46][47][48],41,48,49,50,51,52], including different carriers for a better efficacy [10,33,52,53,54,55][10][29][48][49][50][51]. Preclinical studies have shown, both in vitro and in vivo, that the inhibition of CXCR4 is effective in treating cell proliferation, angiogenesis, tumor growth, and the metastasis of different carcinoma cells [19,25,38,39,40[19][25][34][35][36][37][38][39][40][47][48][49][50][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72],41,42,43,44,51,52,53,54,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76], and it has been reported that CXCR4 blockade increases tumor-infiltrating lymphocytes (TILs) [77][73]. These drugs modify cell migration and invasion and reduce metastasis [38,40,41,54][34][36][37][50]. Additionally, they have also been demonstrated to enhance the sensitivity to chemotherapy or radiotherapy, increasing the reduction in cell viability, apoptosis, tumor growth, and metastasis, including the modulation of the crosstalk between tumor and stromal cells [19,40,41,51,52,55,78][19][36][37][47][48][51][74]. Finally, plerixafor can induce a better immune response against the tumor through the suppression of Treg cells and the regulation of T cell activity [37[33][55],59], and recent studies have reported that CXCR4 inhibition enhances the response to immunotherapy [50,79][46][75]. Clinical trials have provided interesting data to consider CXCR4 antagonists as an alternative in cancer therapy in multicenter, randomized, and even phase II studies. Using these drugs as coadjuvant therapy has been successful, showing acceptable safety and tolerability in patients with advanced refractory tumors and expanding the benefits of chemotherapy or immunotherapy [47,80,81,82][43][76][77][78].

3. CCR5/CCL5 Axis

The use of CCR5-inhibitor drugs in HIV patients is well tolerated, and diverse clinical outcomes have been observed as monotherapy or combined with other antiretroviral drugs (highly active antiretroviral therapy; HAART). The association of CCR5 with cancer progression is unveiling a new perspective on the use of these drugs. CC chemokine receptor 5 (CCR5) is a G-protein-coupled receptor reported in different kinds of carcinomas, with the primary role in the late events of cancer progression, such as metastasis [13,18][13][18]. CCL3 and CCL5 are the main chemokines that bind to CCR5, forming the CCL3/CCR5 and CCL5/CCR5 activation axes. These chemokines are mainly involved in inflammation, promoting the recruitment of leukocytes to injury sites [26][79]. The CCR5/CCL5 axis has protumor effects, and the low expression of these proteins can lead to a better prognosis [83][80]. In carcinomas, some authors have described the relationship between high levels of CCL5 or CCR5 expression in tumors and advanced stages [12[12][13][81][82][83],13,84,85,86], including a proangiogenic role [87][84] and the stimulation of cancer stem cells [88][85]. Regarding immune modulation, CCL5 can differentiate leukocytes to a protumorigenic profile [89][86] and can inhibit the antitumorigenic role of CD8+ lymphocytes [90][87] but can also modulate the activation of Tregs [18] and myeloid-derived suppressor cells [91][88]. CCL5 was reported as an inducer of cell migration and invasion [92][89], leading to metastasis [93][90]. The aggressiveness of CCL5-releasing tumors relies on the fact that they are more aggressive because CCL5 promotes invasion, migration, and metastasis in CCR5-high-expressing tumors. CCR5 inhibition has demonstrated promising results in controlling cancer development and progression in preclinical studies [18,20,22,93,94,95,96,97][18][20][22][90][91][92][93][94]. Maraviroc is a specific small-molecule antagonist of the CCR5 used in preclinical and clinical cancer studies. CCR5 inhibitors were tested to treat liver, pancreatic, and breast cancer cells, showing apoptosis induction, reduced cell invasion and metastasis, and increased survival [20,93,98][20][90][95]. In addition, some studies reported that CCR5 inhibition could modulate the immune response, diminishing Treg infiltration [99,100][96][97]. It was reported that the inhibition of CCR5 in colorectal cancer cells, as a single agent, can inhibit proliferation and migration but failed to inhibit metastasis in vivo [101][98]. However, a study reported that maraviroc could inhibit metastasis in an animal model of colorectal cancer. These contradictory results are probably related to the promiscuity of chemokine receptors and chemokines, suggesting that drugs with dual or multiple inhibitions, or combined therapies (immunotherapy or chemotherapy), could have a better effect against cancer progression and metastasis. Recent preclinical studies have reported that the combination of CCR5 antagonists with anti-PD-L1 can inhibit tumor growth and enhance the therapy outcome in several types of cancer [100,102][97][99]. A few reported clinical trials are using CCR5 antagonists [103][100]. They are in phase I and use maraviroc.

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