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Non-effector Cell Pathways

CCR2/CCR5: stimulate immunosuppressive cell trafficking through the stroma

Chemokine (C-C motif) receptor 2 (CCR2) and 5 (CCR5) regulate the recruitment of immunosuppressive cells through the stroma.1,2 CCR2 and CCR5 are both expressed on the surface of T cells, regulatory T cells (Tregs), monocytes, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs).3-8 Chemokine (C-C motif) ligand 2 (CCL2) and 5 (CCL5) are the ligands for CCR2 and CCR5, respectively.2,9

Expressed by tumor and stromal cells, CCL2 and CCL5 interact with CCR2 and CCR5, respectively, to promote the trafficking and infiltration of immunosuppressive Tregs, TAMs, and MDSCs.1,2,4,8-11 For example, tumors utilize signaling through CCR2 to mobilize inflammatory monocytes from the bone marrow into the blood and to sites of inflammation where they infiltrate into the tumor microenvironment. Monocytes can differentiate into protumor macrophages, such as TAMs, which can suppress cytotoxic T-cell proliferation and function.9,11,12 In addition, CCR5 can stimulate the differentiation of monocytes into protumor TAMs and induce the differentiation of MDSCs.2 CCR2, CCR5, and their ligands may be elevated in certain advanced solid tumors and may enhance tumor cell survival.9,13,14

Preclinical data suggest that depletion or blockade of CCR2 and CCR5, individually or in combination, can decrease the infiltration of MDSCs, TAMs, and Tregs to the tumor microenvironment.10,11,15-17

CD73: tipping the immune balance to a suppressive environment

CD73 is a cell-surface enzyme on regulatory T cells (Tregs), where it is a critical checkpoint in the conversion of immune-activating ATP into immunosuppressive adenosine.18 Tregs act to limit the immune response, and the release of adenosine helps Tregs shut down immune activity.19,20

Cancer exploits the function of CD73 to reduce antitumor immunity. Like Tregs, tumor cells express CD73 and release adenosine into the tumor microenvironment.21-23 In cellular studies, adenosine powerfully inhibits the antitumor immune response, including proliferation and production of cytokines.18

Preclinical research has identified tumor-derived CD73 as a contributor to immune escape in cancer, and inhibition of CD73 activity can stimulate T-cell activity.24

CSF1R: stimulates immunosuppression in the tumor microenvironment

Colony-stimulating factor 1 receptor (CSF1R) is a cell-surface receptor expressed by macrophages and other cells of the myeloid lineage.25

In the tumor microenvironment, some macrophages evolve from antitumor to protumor in their activity.26 These are called tumor-associated macrophages (TAMs). TAMs promote cancer survival and drive immunosuppression, supporting tumor growth.26

CSF1, the ligand for CSF1R, is a dominant regulator of macrophage differentiation and function.27 In cancer patients, high CSF1 concentrations are associated with poorer prognosis.27,28 Mouse models have shown that tumor cells use CSF1 to target CSF1R on macrophages, stimulating the development and survival of TAMs.29

In preclinical studies, blockade of CSF1R—depriving CSF1 of its target receptor—resulted in depletion of TAMs and improved T-cell responses.30,31

IDO1: metabolizes cellular fuel to drive immune suppression

Indoleamine 2,3-dioxygenase-1 (IDO1) is an enzyme expressed in antigen-presenting cells (APCs).32,33 Metabolic enzymes, such as IDO1, require activation by a cofactor.34 The activation of IDO1 is determined by the dynamic binding of its cofactor.35 When bound, activated IDO1 metabolizes tryptophan, an amino acid necessary for cell survival, into immunosuppressive kynurenine.32,36 Normally, the production of immunosuppressive kynurenine acts as a counterbalance to prevent overactivation of the immune response.33,37,38

Tumors can hijack this immunosuppressive process. They evolve to increase IDO1 expression in both tumor cells and APCs.32,39-41 Upregulation of IDO1 depletes tryptophan and generates elevated levels of kynurenine.42 This suppresses T-cell proliferation and promotes regulatory T cell (Treg) development, which helps tumor cells survive.43-45 In a wide variety of hematologic malignancies and solid tumors, increased IDO1 expression is associated with poorer prognosis and outcomes.45-50

As shown in preclinical studies, the inhibition of IDO1 can reduce the number of immunosuppressive Tregs and restore cytotoxic T-cell function.45,51 Furthermore, preclinical data suggest that inhibition of both IDO1 and an immune checkpoint pathway may synergistically improve T-cell proliferation and reduce Treg accumulation.44

IL-8: recruits immunosuppressive MDSCs to the stromal barrier and promotes tumor growth

Interleukin-8 (IL-8) is a chemokine produced by macrophages, monocytes, and stromal cells.52 IL-8 promotes the recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) by binding to G protein–coupled receptors chemokine (C-X-C motif) receptor 1 (CXCR1) and 2 (CXCR2).53,54 During the normal healing process, IL-8 also activates the angiogenic response to generate new blood vessels.55

Both tumor and tumor-associated stromal cells can upregulate production of IL-8.53,55-57 Tumor-derived IL-8 can cause MDSCs to migrate to the tumor microenvironment, where they suppress the antitumor immune response and expand the stroma.55,58 Tumors can use the stroma as a barrier to prevent immune recognition and subsequent T-cell infiltration.59-61 In addition, tumor-derived IL-8 acts as a potent factor that promotes both angiogenesis and tumor metastasis.55,62

Elevated levels of IL-8 are associated with poorer prognosis in a wide range of tumor types.63,64

Preclinical studies suggest that blockade of IL-8 signaling reduces angiogenesis and the recruitment of CXCR1- and CXCR2-expressing MDSCs to the stromal barrier and tumor microenvironment.53,62,65

NLRP3: assembles the inflammasome, a key mediator of innate immunity

Nucleotide-binding oligomeritzation domain-like receptor family, pyrin domain containing 3 (NLRP3) is a protein expressed in antigen-presenting cells (APCs) such as dendritic cells (DCs), monocytes, and macrophages.66 NLRP3 is involved in the assembly of the NLRP3 inflammasome, a protein complex that is a key mediator of innate immunity and the priming of T cells.67,68

NLRP3 expression is first induced by inflammatory signals.69 Subsequently, factors released during tumor cell death, such as adenosine triphosphate (ATP), activate NLRP3 to catalyze the assembly of the NLRP3 inflammasome68,70 Once assembled, the inflammasome converts inactive IL-1β and IL-18 into their mature, active forms.71 These cytokines initiate APC priming as well as activation of natural killer (NK) and cytotoxic T cells, leading to increased recruitment and antitumor function of these primary effector cells.67,68,72,73 As the expression and activation of NLRP3 requires 2 separate inflammatory signals, full activation of the inflammasome may be restricted to sites of inflammation. This may help avoid damage to healthy cells.74,75

Preclinical studies suggest that the NLRP3 inflammasome can activate NK cells and initiate the priming of T cells, which promotes tumor inflammation and enhances antitumor function.67,68,76

STING: stimulates APCs to activate cytotoxic T cells

The stimulator of interferon genes (STING) is an intracellular protein expressed in antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages, as well as other cell types.77,78 STING serves as an innate immune activator that directly stimulates APCs to drive cytotoxic T-cell activity.78

STING is triggered when an intracellular-sensing protein detects DNA from pathogens or dying tumor cells.79,80 Activation of STING leads to the production and secretion of proinflammatory cytokines, including interferons (IFNs) and tumor necrosis factor α (TNFα), which can all increase antitumor immunity.79,81 IFNs promote tumor inflammation.82,83 They can stimulate APCs to activate T cells, initiating T-cell proliferation and trafficking to the tumor microenvironment.80,84 IFNs can also amplify the antitumor function of natural killer (NK) and cytotoxic T cells, as well as promote the survival of memory T cells.78,85,86 STING can also stimulate NLRP3 (NOD-like receptor family, pyrin domain containing 3) to assemble the NLRP3 inflammasome, which leads to the production of additional cytokines.87

Reduced expression of STING may be associated with increased metastasis of tumor cells.88-90 Preclinical data suggest that activation of STING can increase priming of T cells, leading to increased T-cell activation and an inflamed tumor microenvironment.80,82-84 Furthermore, mouse models indicate that activation of STING during simultaneous blockade of immune checkpoint receptors may synergistically promote the antitumor immune response.91,92

TGFR: promotes immunosuppression and metastasis of tumor cells

Transforming growth factor beta receptor (TGFR) is a cytokine receptor that plays a role in inhibiting immune activation.93,94 It consists of 2 receptor dimers, transforming growth factor beta (TGFβ) receptor 1 (TGFR1) and TGFβ receptor 2 (TGFR2), which are expressed on the surface of tumor cells as well as immune cells, such as regulatory T cells (Tregs).94-96 TGFR activation has 2 stages. First, TGFR2 interacts with the potent immunosuppressive cytokine TGFβ. This complex then binds to TGFR1, initiating signaling of multiple processes, including suppression of immune activity and cellular migration.94,97,98

In the tumor microenvironment, TGFR-TGFβ signaling can promote the development of Tregs, altering the balance between Tregs and cytotoxic T cells.93,94 In addition to this Treg-mediated suppression, activation of TGFR expressed on natural killer (NK) and cytotoxic T cells can inhibit the development and antitumor activity of these effector cells, further dampening the immune response.94,99-101 The TGFR-TGFβ interaction can also promote tumor cell invasion and metastasis.102

In multiple tumor types, elevated levels of TGFβ have been associated with a poorer prognosis.103

Preclinical data suggest that inhibiting TGFR activity can reduce the number of immunosuppressive Tregs infiltrating the tumor, increasing the activity of cytotoxic T cells and NK cells.94

Research to further understand these pathways is ongoing.


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