Anti-CCR5 Therapy, Breast Cancer and Its Microenvironment

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1		Andrea Pagani	--	3492	2022-11-24 12:19:04	\|
2	*	Andrea Pagani	Meta information modification	3492	2022-11-26 18:52:02	\| \|
3	update layout	Rita Xu	-40 word(s)	3452	2022-11-28 02:51:47	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms232214159

Breast cancer represents the most common malignancy among women in the world. The local microenvironment around the tumor plays a great role in cancer progression and invasion, representing a promising therapeutic target. CCL5 is a potent chemokine with a physiological role of immune cell attraction and has gained particular attention in R&D for breast cancer treatment. Its receptor, CCR5, is a well-known co-factor for HIV entry through the cell membrane and CCR5 blocking represents a mainstay of HIV treatment. Interestingly, CCL5 is currently described as key pro-oncogenic factor, especially in breast cancer. Several studies blocking the CCL5/CCR5 axis show cancer cells become less invasive and less malignant, with less oncogenic extracellular matrices.

breast cancer tumor microenvironment CCL5

1. Background

Breast cancer is one of the most common cancers worldwide. While early breast cancer is generally curable, there are particularly malignant tumors, such as triple-negative breast cancer (TNBC), whose pathophysiology is still unknown, and an effective therapeutic strategy has yet to be identified ^[1]. Recently, great progress has been made in the fight against breast cancer. With a multidisciplinary approach, the quality of treatment has significantly improved, and the intensity of local and systemic therapy could be significantly reduced ^[2].

Tumor growth and invasion occur at the expense of surrounding healthy tissues, which represent the tumor microenvironment (TME). In the past, no particular importance was given to the TME, which was not thought to have a particular role in breast cancer etiology. The local microenvironment has become a key element only recently, actively participating in cancer progression and representing a fundamental target for new drugs.

At present, surgery, chemotherapy and radiotherapy remain the traditional treatment options for breast cancer. Whereas surgery removes the neoplastic tissue, radiotherapy destroys the tumor and its microenvironment in a non-specific way. Among the most popular and traditional chemotherapies, Anthracyclines (Doxorubicin and Epirubicin) and Taxanes (Docetaxel and Paclitaxel) represent key drugs for breast cancer. Even the alkylating agent cyclophosphamide is a mainstay for different tumor types (e.g. breast, ovarian, breast and blood cancer, retinoblastoma and multiple myeloma). The selective estrogen receptor modulator (SERM) tamoxifen is also a famous drug in oncology and in breast cancer, being able to reduce the development of the tumor mass by blocking the estrogen effects ^[3]^[4]. For postmenopausal women, the most important drugs are the androgen and anabolic steroid Fluoxymesterone, the aromatase inhibitors Exemestane and Anastrozole and Letrozole. Other valuable options are represented by the monoclonal antibodies Trastuzumab, Lapatinib and Bevacizumab, most of the time in combination with Paclitaxel ^[5]. As with all other forms of cancer, prognosis is strongly influenced by the clinical stage at which the cancer is diagnosed. The later the cancer is diagnosed, the more likely it is that the patient will not recover from the disease.

One of the most innovative strategies to fight cancer is represented by Chemokines (CKs). CKs are involved in homeostasis, angiogenesis, metastasis, immune response, inflammation and chemotaxis. Acting as critical regulators of the immune cell population, CKs are classified into four subfamilies, CXC, CC, CX3C and XC, and are either homeostatic or inflammatory. Homeostatic CKs are expressed in the lymphoid tissues as a function of immune cell turnover, while inflammatory cytokines are induced upon tissue damage or infection ^[6]. Within these, the CC motif ligand 5 (CCL5) chemokine (8 kDa) belongs to the CC subfamily and is also known as RANTES (Regulated upon Activation, Normal T-Cell Expressed and Presumably Secreted). By acting as a classical chemotactic cytokine for T cells, eosinophils, basophils and other cells, CCL5 recruits leukocytes to the site of inflammation, induces proliferation of NK cells and is an HIV-suppressive factor released from CD8+ T cells ^[7]. The receptor with the highest affinity for CCL5 is the CC motif chemokine receptor 5 (CCR5), being mainly expressed in T cells, smooth muscle endothelial cells, epithelial cells and parenchymal cells. The CCL5/CCR5 interaction facilitates inflammation, adhesion and migration of T cells in immune responses. CCR5 is involved in chronic diseases, cancers and COVID-19 infection ^[8].

In the healthy breast, with the exception of lactating mothers, CCL5 does not exist normally ^[9]. During lactation, CCL5 is expressed and attracts maternal leukocytes to be included in colostrum ^[10]. There is a wealth of evidence showing that CCL5 is co-opted in breast cancer ^[11] and in many other types of tumors, such as pancreatic ^[12], ovarian ^[13], prostate ^[14] and glioma cancer ^[15]. In vitro and in vivo tests show that blocking or knocking down CCL5/CCR5 is detrimental to tumors such breast cancer and limits metastases ^[16]^[17]^[18]. The possibility of targeting the CCL5/CCR5 axis and inducing an anti-tumor environment is therefore real but challenging. However, a CCR5 blocker that can be part of cancer therapy has yet to be developed.

After introducing the importance of the TME in breast cancer and the CCL5/CCR5 axis, authors highlight the main barriers and hurdles for the clinical adoption of anti-CCR5 therapy in breast cancer. The first hurdle is represented by the great variety of oncological functions of CCR5, which are not yet fully identified. Secondly, the lack of a clear therapeutic window for the application of CCR5 blockers makes the timing of treating the tumor and its microenvironment very complicated. The third and maybe the most difficult hurdle is the uncertainty about which part of the cascade is best to target for the most effective, least problematic pharmaceutical impact. A deep knowledge of all up- and downstream pathways involved in breast cancer is key to understanding which stage of the cascade has to be addressed. Since the role of CCR5 as a coreceptor for HIV has been completely characterized, a competitive CCR5 blocker named Maraviroc is currently used as effective therapeutical element for HIV patients. However, a simple pivot of Maraviroc to cancer therapy is not feasible, due to possible drug interactions with chemotherapeutic agents.

Altogether, the CCL5/CCR5 axis is becoming a valuable therapeutic option. The literature claims that blocking the CCL5/CCR5 connection results in smaller tumors, fewer metastases and longer survival. Despite this promising profile, no CCR5 blocker has been utilized in cancer therapy. Because of the absence of clear publications about this topic, researchers decided to create such a manuscript to fill this void, mainly through the lens of breast carcinoma.

2. Breast Cancer and the Importance of the Tumor Microenvironment

The concept of cancer as a single mass of neoplastic cells has recently changed radically. Breast cancer consists not only of mutated cells, but also of a surrounding altered microenvironment which is key for tumor development. Besides breast cancer cells, suppressive immune cells, soluble factors and the extracellular matrix (ECM) act together to promote tumor progression and metastasis. The cellular component of this microenvironment is mainly represented by cancer-associated fibroblasts (CAFs), mesenchymal stromal cells (MSCs), endothelial cells (ECs), pericytes and immune cells ^[19]. Different molecular alterations and aberrant signaling pathways result in the proliferation of altered stromal cells in the contact zone between the tumor and its microenvironment ^[20]^[21]. The interaction between cancer cells and the TME is the current focus of cancer research, in order to develop new clinical implications.

As researchers in this field, researchers always studied breast cancer as a real “onco-cellular” system composed of a tumor and its bordering tissues. At the contact zone of the tumor mass, cancer cells and neighboring non-cancer cells are connected with each other. Provenzano et al. ^[22] reported that the local microenvironment could be composed of different collagen layers named TACS-1, -2 and -3, which radiate out 90° perpendicular to the contact zone of the tumor. In the recent work ^[23], researchers hypothesized that the interaction at the TNBC tumor boundary between adipose stem cells (ASCs) and local fibroblasts (MDA-MB-231 cells) produces high levels of CCL5. This allowed researchers to demonstrate that resident fibroblasts react to CCL5 production by generating a striated ECM rich in collagen type VI (Col6a1^−/−) within the TME. Because of the sensitivity of the TME to radiotherapy (RT) ^[24], researchers even highlighted the possibility of targeting the breast cancer and its TME with low doses of RT (5Gy). The findings showed that irradiated cells in the TNBC microenvironment produce an ECM which contains lower proportions of oncogenic collagen VI compared to the non-irradiated one ^[25]. By affecting the TME and inducing an inflammatory reaction, RT impacts the production of collagen, promotes tumor vascularization and leads to cell death.

Because of all these findings, the TME could be represented by distinct layers mainly composed of collagen VI (Col6a1^−/−) and should be strongly supported by the CCL5-mediated activity of resident fibroblasts. The addition of low doses of adjuvant RT in breast cancer could be a promising therapeutical tool to reduce collagen VI and maybe impact CCL5. This scenario represents an unreported role of RT in breast cancer and is one of the most hopeful research focuses triggered by the group.

3. The Molecule CCL5, the Receptor CCR5 and Its Structural Mutation That Confers HIV Resistance

CCL5 is a powerful chemoattractant with a physiologic role in recruiting immune cells in inflammatory or allergic circumstances ^[26]. CCL5 binds with high affinity to its main receptor CCR5, but also to CCR1, -3, -4, CD44 and GPR75. CCR5 is a seven-transmembrane G-protein-coupled receptor expressed on various cell types (e.g. T cells, macrophages, dendritic cells, eosinophils and microglia). The interaction between CCR5 and its high-affinity molecules (e.g. CCL5, CCL3, CCL4 and CCL8) results in G protein activation and a following boost of different signal transduction pathways. One of these is represented by NF-kB (Nuclear Factor kappa-light-chain-enhancer), in which CCL5 represents an important target gene ^[27].

As is widely reported, CCR5 is a critical co-receptor used by HIV in early-stage infection ^[28]. Blocking CCR5 in HIV patients is a valuable therapeutical option and is relatively innocuous; the CCR5-delta 32 mutation is responsible for HIV resistance and causes the CCR5 extracellular co-receptor to be smaller than usual, and thus defective ^[29]. The mutation is chiefly prevalent among those descended from Northern Europeans, and Sweden in particular, where the mutation is homozygous in 1% of the population. In total, 10–15% of Europeans have one copy of the mutated gene, which does not confer immunity to HIV, but slows the rate of AIDS development ^[30]. Despite the number of preclinical and clinical trials ^[31], there is no definitive evidence that CCR5 blockers give cancer resistance on HIV patients.

4. The CCL5/CCR5 Axis in Human Diseases and Its Related Downstream and Upstream Pathways

Recently, Zeng et al. summarized the different downstream and upstream pathways correlated with the CCL5/CCR5 axis ^[32]. The main downstream pathways of CCL5/CCR5 are represented by NF-kB, PI3K/AKT, HIF-1alpha, RAS-ERK-MEK, JAK-STAT and TGF-Beta-Smad. Between these, the activation of AKT and GSK-3Beta through PI3K phosphorylation allows the expression of different downstream proteins, such as Bcl2, Beta-Catenin and Cyclin D, playing a key role in several mechanisms of the cell cycle and cellular apoptosis. In addition, the CCL5/CCR5 axis can support the stability and accumulation of HIF-1alpha, which initiates a cascade of different processes related to angiogenesis and cellular regeneration ^[33]^[34]^[35]. Finally, the activation of the NF-kB pathway through CCL5/CCR5 upregulates the expression levels of Inhibitor of Apoptosis Proteins (IAPs), FLICE-like inhibitory proteins (FLIPs) and matrix metalloproteinase (MMP).

On the other hand, the most important upstream pathways include plasminogen activator inhibitor-1, SOCS-1, Rig1 and Kruppel-like zinc-finger transcription factor 5 (KLF5) ^[27]^[36]^[37]^[38]^[39]. Other upstream stimuli of CCL5 are the enhancer of zeste homolog 2 (EZH2), which regulates macrophage-mediated cancer cell progression and migration; HER2 and PTEN, which are associated with cancer progression; and the angiotensin 2 (Ang2), which enhances the transcription of CCL5 and prolongs the immune response ^[40]^[41]^[42]^[43]. When one or more of these regulators interact incorrectly with the CCL5/CCR5 axis, the body loses its homeostasis and an inflammatory process is established: the tissue fills with common inflammatory molecules such as TNFs, ILs and TGF-Beta, and the inflammatory process initiates a cascade of events leading to disease. In addition to cancer and inflammation, different viral infections, diabetes, Alzheimer’s disease and endometriosis are correlated with the CCL5/CCR5 axis.

As mentioned at the beginning of the manuscript, the relationship between the tumor and its microenvironment is key. Due to the presence of CAFs, MSCs, ECs, different types of immune cells within the TME and the several immunological functions of CCR5, the possibility of regulating the TME through an anti-CCR5 drug is challenging. As thoroughly reported by Jiao ^[31]^[44], CCR5 induces cancer cell homing to metastatic sites, enhancing the pro-inflammatory and -metastatic immune phenotype and even DNA repair mechanisms. In the past, much attention had been paid to the combination of CCR5 inhibitors with canonical checkpoint inhibitors (e.g., pembrolizumab). Schlecker et al. ^[45] highlighted that the synergic effect of these drugs should influence the immunological setting of the TME. Tumor-infiltrating lymphocytes (TILs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), innate lymphoid cells (ILCs), Tregs, mesenchymal stem cells (MSCs) and immature dendritic cells could work synergically and contribute to tumor- and TME-induced immunosuppression ^[46]. The above-mentioned molecules actively express CCR5 and are able to produce CCR5 ligands. MSCs produce CCL3, -4 and 5 and promote metastasis when mixed with breast and colon cancer cells; CD4⁺ Foxp3⁺ Tregs preferentially express CCR5 when compared with CD4⁺ Foxp3⁻ effector T cells; and TAK-779-mediated inhibition reduces Treg migration to tumors, reducing pancreatic tumor size ^[47] Even the absence of CCR5 ligands is associated with reduced infiltration of antigen-specific T cells and associated metastasis. For example, CCL8 is produced by macrophages in the lungs of mice with metastatic primary tumors. The migration of Tregs toward CCL8 ex vivo is reduced in the presence of Maraviroc. Hence, the treatment of mice with Maraviroc reduced the level of CCR5⁺ Tregs and metastatic tumor burden in the lungs ^[48]. Another example is given by CCL3, which binds CCR5 and -1, promoting tumorigenesis through recruitment of pro-tumor macrophages into the TME ^[49]. Because of this, the genetic deletion of CCL3 in macrophages reduces lung metastasis ^[49]. Numerous other ligands (e.g., EGF, CSF1, HGF, CCL2, CXCR4/CXC1l2 and Tie2) support tumor progression in the TME and are promising therapeutic targets ^[50]. From a clinical point of view, a CCR5 blockade with anti-CCR5 antibodies can suppress both the growth of melanoma and its TME and MDSC accumulation in mouse tumor tissues. Furthermore, it was shown that Maraviroc reduces MDSC-induced colon cancer metastasis ^[51].

Above all tumors, breast cancer represents one of the most important and deadliest cancers worldwide. Despite the scarcity of CCL5 in epithelial cells of normal ducts of benign breast lumps, it seems CCL5 is generated during malignant breast transformation ^[9]. Within the tumor and its microenvironment, the enhanced levels of CCL5 activate the PI3K/AKT/mTOR pathway and lead to cellular proliferation and resistance to apoptosis. The main upregulator of cancer cells is represented by the insulin-like growth 1 (IGF-1) pathway that promotes tumor cell invasion and progression. The enhanced levels of CCL5 lead to high GLUT1 expression on the surface of cancer cells and provide enough energy for the proliferation of breast tumor cells as well as angiogenesis. Even other molecules that increase CCL5 levels, such as IL-6 and HER2-PTEN, contribute to breast cancer development ^[32].

In addition to CCL5 levels, even CCR5 receptor expression is higher in breast cancer tissues compared to normal tissues. When expressed, CCR5 correlates with increased migratory abilities and cancer invasion ^[18]. Jiao et al. ^[44] reported that CCR5+ breast cancer cells are able to form mammospheres and tumors in mice, with high expression of DNA repair pathways. Furthermore, high levels of CCR5 indicate enhanced DNA repair gene levels in response to DNA-damaging agents. Altogether, the interaction of the up- and downstream pathways with the CCL5/CCR5 axis and its impact are under investigation, and the research conducted so far in this direction is up-and-coming.

In the next chapter, authors report the main hurdles in breast cancer therapy using CKs. The first one is represented by the great variety of oncological functions of CCR5, which are not fully understand. The second barrier concerns the lack of a clear therapeutic window for the application of CCL5/CCR5 blockers. The third and the most difficult hurdle is the uncertainty about which part of the cascade is best to target for the most effective, least problematic pharmaceutical impact.

5. Barriers and Hurdles between Anti-CCR5 Therapy, Breast Cancer and its Microenvironment

As mentioned before, the connection between CCL5 and CCR5 facilitates cancer progression and invasion. CCL5/CCR5 axis increases tumor dimension, induces ECM remodeling, cellular migration and metastasis formation, supports cellular stemness and expansion along the tumor borders, confers therapeutical resistance on cancer cells, decreases DNA damage, deregulates cellular energetics, promotes angiogenesis, recruits immune and stromal cells and induces the immunosuppressive polarization of macrophages ^[27]. There is an unmatched levels of evidence supporting the participation of all CKs other than CCL5 in the construction, development and operation of the primary invasive breast tumor ^[11]. As mentioned before, CCL5 is also ubiquitous across breast cancer cases. The complete spectrum of CCL5/CCR5 signaling is not known, even because high levels of CCL5 are congruent with longer disease-free survival ^[52]. Hence, the group speculate that CCL5 acts as a double-edge-sword by initially fueling tumor development and then recruiting antitumor cell populations to the zone. Such a role could be worth considering before effecting a complete CCR5 blockade. Inhibiting CCL5/CCR5 signaling does not tipically come with drastic side effects or compensatory measures, but the inhibitory agents available for HIV have side effects and negative drug interactions with chemotherapy.

The second barrier is represented by the lack of a clear therapeutic window in a breast cancer patient. It has been recently established that blocking either CCL5 or CCR5 immediately after diagnosis would stall cancer cell invasion ^[53]^[54]^[55]. However, the impact of CCL5 on the local stromal fibroblasts could better inform an effective therapeutic window. CCR5 signaling induces local fibroblasts to create linear collagen type VI, leading away from the tumor and into the healthy stroma. The linear, aligned collagen is formally known as a "tumor associated collagen signature" (TACS), a system classing three distinct collagen patterns radiating from the tumor body [22]. Researchers recently showed that linear collagen VI is dependent on CCL5 signaling, as the structural linearity and presence of Collagen VI were both significantly decreased upon adding a CCL5 monoclonal antibody to the test conditions. Since the Collagen VI isoform is not found in the physiological breast, and since it signifies an increase in malignancy, it is an a priori biomarker for CCR5 signaling. By the time the CCL5-dependent collagen VI surrounds the tumor, it is likely there are already metastases^[56]. Moreover, blocking CCR5 after that Collagen VI has been formed will not destroy Collagen VI. The therapeutic window for blocking CCR5 and Collagen VI production has been missed. Hence, there is evidence that CCR5 should be blocked as early as possible after the diagnosis. The pathway to CCL5 production and binding to CCR5 has many moving parts. Is taking, for example, Maraviroc for cancer treatment a viable option? If not, what part of the CCR5 pathway should researchers target for tumor therapy? The answer is complex and still unknown.

The third and last barrier is represented by the uncertainty about which part of the signaling pathway would be best to target for the most effective impact. In the case of CCL5/CCR5, the production of CCL5, free floating CCL5, substrate/ligand binding or expression of CCR5 are all targetable stages. To affect the cellular source of CCL5 is to inhibit the cell-cell binding of adipose-derived stem cells (ADSCs) and cancer cells, an extremely involved and impractical goal. Meanwhile, the antibodies developed to bind extracellular CCL5 have found their main application in in-vitro research ^[57]. However, it would take an incredible amount of monoclonal antibody given intravenously to reach the breast and have a quantifiable effect. Most approved drugs act as competitive blocker of their receptor. Considering the advent of mRNA therapy, in the near future researchers could have the possibility to limit CCR5 expression at the RNA level.

6. Conclusions

The TME is a key element in cancer invasion and progression and is the focus for developing new therapeutical strategies. The possibility of targeting a tumor and its TME with CKs via the CCL5/CCR5 axis is promising, and new therapeutical technologies are under investigation. It is agreed scientifically that blocking CCR5 signaling in breast cancer would have a massive impact on tumor development. The main barriers to this are represented by unknown side effects of blocking CCR5 in a cancer setting, uncertain dose timing and duration and an unclear pharmaceutical mechanism of action for a cancer CCR5 blocker. Considering these three limitations, it makes sense why CCR5 blocking is not yet a mainstay of cancer treatment. mRNA could be the new solution to this old question. Given the sheer wealth of detailed research showing CCL5 as a pro-tumor chemokine, it could be an ideal candidate marker for a highly impactful new mRNA-based drug.

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