What is the role of Chemokines in tumor immunity?
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What is the role of Chemokines in tumor immunity?
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What is the role of Chemokines in tumor immunity?
Chemokines are a subfamily of cytokines responsible for immune cell trafficking and lymphoid tissue development.
Currently, 50 different chemokines have been reported, which can be divided into four major categories, namely C, CC, CXC and CX3C chemokines according to the position of the first two cysteine ( C ) residues of their main protein structures factor.
Each immune cell subset has a distinct pattern of chemokine receptor expression, which allows them to respond differently to chemokines and migrate according to the specific needs of each environment.
In cancer, they play a key role in the pattern of immune cell migration into the tumor, thereby shaping the immune signature of the tumor microenvironment, often towards a pro-tumorigenic state.
Furthermore , chemokines can directly target non-immune cells in the tumor microenvironment, including tumor cells, stromal cells, and vascular endothelial cells.
Thus, chemokines are involved in a variety of cancer development processes, such as angiogenesis, metastasis, cancer cell proliferation, stemness, and invasiveness, and are key determinants of disease progression with a large impact on patient prognosis and treatment response.
Due to their important regulatory functions in cancer cells and immune-infiltrating cells, chemokine ligands and their receptors are very powerful therapeutic targets.
The role of chemokines in tumor immunity
3Immune evasion and recruitment of immunosuppressive cells
Chemokines play a crucial role in directing immune cell migration, which is required to initiate and deliver an effective antitumor immune response.
Chemokine secretion is often altered in the TME, and aberrant chemokine distribution can promote the differentiation and infiltration of immunosuppressive tumor-promoting cells ( i.e., Treg cells, MDSCs, and TAMs ) into tumors.
Treg cells have higher expression of the chemokine receptor CCR4 than other CD4+ T cells, which respond to CCL22, a chemokine produced by TAMs and primary tumor cells.
In addition to CCR4, Treg cells can express other chemokine receptors that can mediate their infiltration into the TME, such as CCR5 or CCR10, and its ligand CCL28 is present in the hypoxic region of the TME.
Macrophages are mainly recruited to the TME through the CCL2–CCR2 signaling pathway.
Tumor expression of CCL2 correlates with the number of TAMs in many tumors and is often associated with poor patient prognosis.
Like Treg cells, TAMs can also inhibit tumor-associated antigen ( TAA )-specific CD8+ T cell activation.
Much like TAMs, myeloid-derived suppressor cells (MDSCs) can also be recruited into TEMs via CCL2–CCR2 signaling.
In addition , other chemokines that induce monocyte recruitment to tumors are CCL5, CCL7, CCL15 , CXCL8 and CXCL12.
Plasmacytoid dendritic cells ( pDCs ) are rare immune cells that also suppress antitumor immune responses.
Tumor and stromal cells produce CXCL12, a ligand for the chemokine receptor CXCR4, which is expressed by pDCs.
Therefore, CXCL12 is a key molecule for pDC entry into the TME.
In addition, CXCL12 also exerted a protective effect on pDCs, preventing their apoptosis and prolonging their immunosuppressive effects.
Tumor growth and progression
Several studies have shown that chemokine signaling systems are involved in tumor growth and progression through different mechanisms.
Interactions between chemokine receptors expressed by cancer cells and their respective ligands secreted by tumor-associated fibroblasts, tumor cells, and TME-infiltrating immune cells can directly activate signaling pathways such as PI3K/AKT and ERK 1/2, resulting in Cancer cells proliferate.
Pathological overexpression of chemokine receptors on tumor cells and secretion of chemokine ligands in the TME can exacerbate these effects.
In addition, chemokines can maintain cancer cell survival by creating an imbalance between pro- and anti-apoptotic proteins in tumor cells, such as downregulating Bcl-2 expression or inhibiting caspase-3 and caspase-9 activation, thereby avoiding tumors apoptosis.
Chemokine recruitment by certain immune cells also contributes to tumorigenesis. IL-22-secreting T helper cells ( TH22 ), a common immune cell subset in the TME, have been shown to support tumorigenesis through multiple pathways, especially in colon cancer.
They express the chemokine receptor CCR6 and migrate towards the ligand CCL20 present in the TME, where they are able to increase the stemness and tumorigenic potential of tumor cells through cytokine expression.
Angiogenesis
Chemokines and their respective receptors are considered key regulators of tumor vasculature with dual roles in tumor angiogenesis.
Depending on the presence or absence of an ELR ( Glu-Leu-Arg ) motif at the N-terminus, CXC chemokines can be divided into two categories: ELR+ chemokines and ELR− chemokines. ELR+CXC chemokines, including CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, acting through activation of CXCR1 and CXCR2, have angiogenic effects. In contrast, ELR−CXC chemokines, such as CXCL4, CXCL9, CXCL10, CXCL11, and CXCL14, are considered angiogenesis inhibitors.
Chemokines can act as mediators of tumor angiogenesis by directly interacting with chemokine receptors on endothelial cells, thereby improving migration and proliferation as well as endothelial cell survival. In addition, chemokines may also act indirectly by promoting the recruitment of angiogenic factor-producing leukocytes in the TME, thereby enhancing angiogenesis.
Chemokines can also act synergistically with other angiogenesis-promoting agents, such as vascular endothelial growth factor ( VEGF ).
On the other hand, chemokines also have the activity of inhibiting tumor angiogenesis and endothelial cell proliferation.
For example, CXCL4 and CXCL10 are chemokines with vascular inhibitory properties, including inhibition of angiogenesis induced by fibroblast growth factor and VEGF, and prevention of endothelial cell chemotaxis and proliferation.
Furthermore, the interaction of CXCL9, CXCL10, and CXCL11 with CXCR3-expressing immune cells may recruit cells with vascular inhibitory functions.
Promote transfer
Numerous studies have confirmed the critical role of the chemokine system in tumor metastasis.
Chemokine receptor expression on cancer cells has been reported to determine the site of their metastasis.
The specific chemokines produced at these metastatic sites can promote the migration of circulating cancer cells into the “pre-metastatic niche”, which provides a favorable environment for the growth of metastatic cells.
Multiple chemokines and chemokine receptors have been implicated in metastasis, and the CXCL12/CXCR4 axis represents a key factor in this phenomenon, and its involvement in tumor metastasis has been demonstrated in different tumors.
Examples of other chemokines involved in cancer metastasis are CCR7, which mediates the migration of cancer cells to lymphoid organs by interacting with CCL19 and CCL21 ligands secreted at metastatic sites; CCL28, a ligand for CCR3/CCR10, is associated with breast cancer.
Growth and metastatic spread are associated; CCR10/CCL27 signaling supports melanoma cell adhesion and survival during metastatic spread, and CXCR5/CXCL13 interaction appears to support bone metastasis in prostate cancer.
Chemokine-targeted therapy
Currently, clinically approved drugs targeting chemokines include: anti-CCR4 antibody ( Mogamulizumab ) and CXCR4 antagonist ( Plerixafor, AMD3100 ) for hematological malignancies.
In addition, there are many more diverse efforts targeting different chemokine receptor-ligand axes as cancer therapeutic strategies that have shown great potential and are currently in clinical development.
CCR1
CCR1 is overexpressed in several types of cancer and is associated with increased infiltration and metastasis of immunosuppressive cells.
Most of the therapeutic benefit of targeting CCR1 comes from reducing MDSC infiltration and ultimately inhibiting tumor growth and metastasis.
The selective CCR1 antagonist CCX721 is able to reduce tumor burden and osteolytic lesions in a mouse model of multiple myeloma ( MM ) bone disease by blocking osteoclasts .
Another study reported that inhibition of CCR1 using the receptor antagonist BL5923 inhibited the recruitment of immature myeloid cells, reduced metastatic colon cancer, and significantly prolonged survival in mice with colon cancer liver metastases.
The combination of the CCR1 antagonist CCX9588 with an anti-PD-L1 antibody has proven to be a promising therapeutic approach, as it produces synergistic antitumor effects by inhibiting primary tumor growth and lung metastasis in an orthotopic breast cancer mouse model .
Recently, in a mouse model of ovarian cancer, the small-molecule CCR1 inhibitor UCB35625 was also able to reduce cell migration to the omentum, a site of preferential metastasis for this type of cancer.
Collectively, these results suggest that targeting CCR1 is a viable therapeutic strategy to limit metastasis and delay disease progression.
CCR2, CCL2
The CCL2/CCR2 axis has been shown to recruit immunosuppressive cells, such as MDSCs and metastasis-promoting monocytes , to the TME, and blocking the CCL2/CCR2 axis has shown antitumor effects in several malignancies.
Several studies have focused on the treatment of pancreatic cancer with CCR2 inhibitors, using the oral CCR2 inhibitor PF-04136309 to target TAMs by inhibiting CCR2 signaling in an in vivo mouse model can improve chemotherapy efficacy, block metastasis, and increase antitumor TAM cellular response.
In a phase Ib/II trial ( NCT02732938 ) in metastatic pancreatic ductal adenocarcinoma, the molecule was used in combination with Abraxane ( nab paclitaxel ) and gemcitabine with favorable results.
Another phase II clinical trial evaluating a CCR2 inhibitor in combination with conventional chemotherapy regimen FOLFIRINOX ( FX ) in patients with marginally resectable or locally advanced pancreatic ductal adenocarcinoma confirmed the safety and tolerability of the therapy.
Notably, inhibition of CCR2 using the small molecule CCX872 enhanced the therapeutic efficacy of anti-PD-1/PD-L1 immunotherapy in a mouse model of pancreatic cancer.
Another preclinical study evaluating the CCR2 antagonist RDC018 in hepatocellular carcinoma showed that it inhibited tumor growth and metastasis, reduced postoperative recurrence, and prolonged survival.
CCL2 is the major ligand of the receptor CCR2, and blocking CCL2 has shown antitumor activity in preclinical studies by enhancing the efficacy of radiotherapy and preventing metastasis.
However, the anti-CCL2 mAb carlumab ( CNTO 888 ) failed to demonstrate clinical benefit in phase 1 and 2 clinical trials in solid tumors ( NCT00992186 ) and metastatic prostate cancer ( NCT00537368 ) due to its inability to reduce CCL2 serum levels.
CCR4
In addition to being the major chemokine receptor for regulatory T cells, CCR4 is overexpressed in several T cell malignancies.
The anti-CCR4 antibody mogamulizumab, originally used to treat refractory Hodgkin lymphoma, is currently used in Japan for relapsed adult T-cell leukemia and successfully improved progression-free survival in a phase III trial in cutaneous T-cell lymphoma and quality of life.
Mogamulizumab is a humanized monoclonal antibody with a defucosylated Fc region to enhance effector cell binding capable of inducing the elimination of malignant T cells through antibody-dependent cellular cytotoxicity ( ADCC ).
Two independent clinical trials have shown that Mogamulizumab is safe alone or in combination with the anti-PD-1 antibody Nivolumab in the treatment of advanced or metastatic solid tumors.
Several other CCR4 therapies are currently in development, including anti-CCR4 CAR-T cells, which have been shown to be effective against several T-cell malignancies, and small molecule CCR4 antagonists that can improve the efficacy of anticancer vaccines by preventing Treg induction. potency.
CCR5
The anti-CCR5 humanized monoclonal antibody leronlimab and the small molecule CCR5 inhibitors maraviroc and vicriviroc have shown promising results in several malignancies.
All three drugs blocked the transfer of human breast cancer xenografts in immunodeficient mice and enhanced the cell-killing effects of DNA-damaging chemotherapeutics.
Maraviroc and vicriviroc were also able to reduce cell metastases throughout the body, bone and brain in mouse models of prostate cancer, while Maraviroc restricted the accumulation of cancer-associated fibroblasts in models of colorectal cancer, resulting in reduced tumor growth.
In addition, maraviroc showed promising results in a clinical trial ( MARACON ) that reduced tumor cell growth in colorectal cancer patients refractory to standard chemotherapy, while two other clinical trials evaluated pembrolizumab versus maraviroc or Combined inhibition of Vicriviroc in refractory microsatellite-stabilized colorectal cancer showed prolonged disease stabilization and better-than-expected survival.
Additional clinical trials are currently underway in patients with CCR5+ metastatic cancer to evaluate CCR5 antagonists in combination with other drugs.
CCR7
CCR7 neutralizing therapy has shown promising results in a number of preclinical models. Silencing CCR7 gene expression by siRNA or miRNA resulted in reduced metastasis and tumor growth in prostate, breast, and colorectal cancer models.
An anti-CCR7 monoclonal antibody was shown to induce tumor cell death and reduce or avoid CNS disease in a T-cell lymphocytic leukemia xenograft mouse model, whereas a single-chain anti-CCR7 antibody successfully prevented T cell acuteness in an in vitro model Lymphocytic leukemia cells cross the blood-brain barrier.
CXCR2
The CXCR2–CXCLs axis is an important chemokine, and there are many mechanisms by which the CXCR2–CXCLs axis promotes tumor progression, but the most prominent one is related to neutrophil recruitment to the TME and promotion of angiogenesis.
Neutralization of CXCR2 has shown promising results in various preclinical cancer models, often as part of combination therapy to circumvent chemoresistance.
The CXCR2 inhibitor Navarixin synergized with MAPK inhibition in a melanoma model, while the inhibitor SB225002 improved antiangiogenic therapy with sorafenib in an ovarian tumor model.
The CXCR1 and CXCR2 inhibitor Reparixin, when used in combination with 5-fluorouracil, was also able to improve tumor cell apoptosis and reduce tumor volume in a gastric cancer model.
AZ13381758, a small-molecule inhibitor of CXCR2, reduced metastasis and significantly extended lifespan in a pancreatic ductal adenocarcinoma model when used in combination with gemcitabine.
Currently, seven CXCR2 inhibitors are being investigated in multiple clinical trials, four of which are used to treat metastatic malignancies.
These include AZD5069/AZD9150 for prostate cancer ( Phase 2 ), head and neck squamous cell carcinoma ( Phase 1b/2 ) and pancreatic ductal carcinoma ( Phase 1b/2 ); Reparixin for breast cancer ( Phase 2 ) Navarixin for the treatment of prostate cancer and non-small cell carcinoma ( Phase 2 ); SX-682 for the treatment of Stage III and IV melanoma ( Phase 1 ).
CXCR4
Given the indisputable clinical relevance of CXCR4 to the growth and spread of multiple malignancies, many CXCR4-targeted peptide and non-peptide antagonists have been developed over the past decade.
CXCR4 antagonists, such as AMD3100 and AMD3465, enhance the clinical efficacy of traditional therapies by mediating the transport of tumor cells from the bone marrow milieu.
A phase I/II study in patients with relapsed AML ( NCT00512252 ) presented data showing a correlation between the in vivo efficacy of CXCR4/CXCL12 axis blockade and encouraging response rates.
The humanized CXCR4 antibody PF-06747143 showed strong antitumor effects in various hematological tumor models including NHL, AML and MM.
A Phase I trial ( NCT02954653 ) in patients with acute myeloid lymphoma to evaluate safety and tolerability was unfortunately terminated due to sponsor reasons.
More recently, a phase Ib/II trial ( NCT01359657 ) of another anti-CXCR4 antibody, ulocuplumab ( BMS-936564 ), confirmed that blocking the CXCR4–CXCL12 axis is safe and combined with lenalidomide and dexamethasone in the treatment of recurrent/ Patients with refractory myeloma have a high response rate.
CXCR4 inhibitors have also been shown to have important anticancer potential in solid tumors. Several clinical trials are currently evaluating the clinical benefit of CXCR4 antagonists in patients with glioblastoma.
A phase I/II trial ( NCT01977677 ) investigating the side effects and optimal dose of plerixafor after temozolomide and radiation therapy showed that plerixafor did not observe dose-limiting toxicities and appeared to inhibit CXCL4-mediated angiogenesis after RT , enhancing the effect of radiation therapy.
In addition to brain tumors, AMD3465 was able to prevent breast cancer growth and metastasis in vivo, while the novel cyclic peptide CXCR4 antagonist LY2510924 showed antitumor activity in various solid tumor and metastatic breast cancer preclinical models.
LY2510924 was tested in a Phase 1 trial ( NCT02737072 ) and was well tolerated.
In patients with HER2-negative metastatic breast cancer, a phase I trial ( NCT01837095 ) of the CXCR4 antagonist balixafortide as monotherapy and in combination with other agents yielded promising preliminary results.
Notably, CXCR4 inhibition was also shown to promote strong antitumor T cell responses. CXCR4 blockade in a preclinical model of ovarian cancer significantly increased T cell-mediated antitumor immune responses, giving AMD3100-treated mice a significant survival advantage.
BPRCX807, a selective and potent CXCR4 antagonist, has recently shown promising results in in vitro and in vivo experiments in mouse models of hepatocellular carcinoma.
Summary
Chemokines are a large class of cytokines that coordinate the tropism of immune cell trafficking.
Given the multifaceted roles of chemokines in tumor immune responses and tumor biology, chemokine networks have emerged as potential immunotherapeutic targets.
There are very complex interactions between chemokine receptors and their ligands, and in order to introduce a new generation of chemokine modulation-based immuno-oncology therapeutic strategies, a deep understanding of tumor microenvironment biology and better predictive clinical models are urgently needed .
Despite the challenges, a large number of chemokine receptor inhibitors targeting different chemokine signaling pathways are currently being evaluated in preclinical studies and clinical trials and show promise when combined with conventional chemotherapy or immune checkpoint therapy result.
Therefore, it can be predicted that in the near future, chemokine receptor inhibitors will be used to modulate the composition of the TME and optimize the patient’s immune response, bringing hope to tumor patients.
References:
1. Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy. Int J Mol Sci. 2021 Sep; 22(18): 9804.
What is the role of Chemokines in tumor immunity?
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