The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity
Abstract
:Simple Summary
Abstract
1. Introduction
2. Biological Aspects of NK Cell Cytotoxicity
2.1. NK Cells’ Metabolism
2.2. NK Cells Recruitment to the Tumor Site
2.3. Formation of the Lytic NK-Cell Immunological Synapse
2.3.1. Recognition Stage
2.3.2. Effector Stage
2.3.3. Termination Stage
2.4. NK Cells’ Cytokine Production
3. Characteristics of the Tumor Microenvironment
3.1. Tumor Hypoxia and Acidosis
3.2. Oxidative Stress
3.3. Cytokines
3.4. Amino Acid Deprivation
3.5. Alterations in the Key Enzymes of Lipid and Adenosine Metabolism
4. How Tumor Microenvironment Factors Inhibit NK Cells
4.1. NK Cells’ Metabolism
4.2. NK Cells Recruitment to the Tumor Site
4.3. NK Cells’ Lytic Synapse
4.3.1. Recognition Stage
4.3.2. Effector Stage
4.4. NK Cells’ Cytokines and Chemokines Production
5. Strategies to Overcome the Inhibitory Effects of TME on NK Cell Functions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Source of Chemokines | Chemokines | Chemokine Receptor | Chemokine Receptor Expression on the NK Cell Population | |
---|---|---|---|---|
NKbright | NKdim | |||
Tumor | CCL3, CCL5, CCL7, CCL9, CCL14-16, CCL23 | CCR1 | + | − |
CXCL1-3, CXCL5-8 | CXCR2 | − | ++ | |
CXCL9-11 | CXCR3 | ++ | − | |
CXCL12 | CXCR4 | + | ++ | |
CXCL8 | CXCR1 | − | ++ | |
CX3CL1 | CX3CR1 | − | ++ | |
CCL3, CCL4 | CCR5 | ++ | + | |
Lymph nodes | CCL19, CCL21 | CCR7 | ++ | − |
TME Factor | Strategies | Examples of Clinical Trials (NCT: ClinicalTrials.gov Identifier) |
---|---|---|
Hypoxia | Priming of NK cells with IL-2 increases the expression of activating receptors and thus overcomes the inhibitory effects of hypoxia [244,245]. | Natural Killer Cells Plus IL-2 Following Chemotherapy to Treat Advanced Melanoma or Kidney Cancer NCT00328861 Intraperitoneal Delivery of Adaptive Natural Killer (NK) Cells (FATE-NK100) With Intraperitoneal Interleukin-2 in Women with Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer NCT03213964 |
Modification of NK cells to increase ADCC potential and activity—high-affinity NK cells (haNK) expressing CD16 and IL-2 are resistant to acute hypoxia [246]. | Phase 1 Study of haNK™ for Infusion in Subjects with Metastatic or Locally Advanced Solid Tumors NCT03027128 | |
Inhibition of HIF-1α (either by genetic modifications or small molecular HIF-1α inhibitor) enhances effector functions of activated NK cells (degranulation, production of IFN-γ and TNF-α [247]. | None | |
Lactic acid/Low pH | Genetic blockade of LDHA (mice with LDHA deficiency) heightens infiltration of NK cells in the melanoma tumors. Infiltrated NK cells have an elevated production of IFN-γ and granzyme B [199]. Novel LDHA inhibitor reduces lactate production, thus decrease TME acidity [248]. | None |
Bicarbonate monotherapy neutralises tumor acidity and increases effector cells infiltration [249,250]. | Extended Use of Sodium Bicarbonate in Patients with Cancer NCT02531919 | |
Blocking the mitochondrial ROS accumulation to prevent NK cells mitochondria dysfunction and apoptosis [162]. | None | |
Glucose depletion | FBP1 inhibition during tumor promotion, but not tumor progression, can restore NK cell function [168]. | None |
GSK-3 inhibitors, CHIR99021, blocks proteasomal degradation of cMYC and thus promotes glucose consumption in NK cells [251]. CHIR99021 was shown to improve NK-cells function in ovarian cancer [251]. Moreover, other GSK-3 inhibitors, including LY-2090314 were shown to augment NK cells cytotoxicity in AML patients [252]. | Phase 1 trials evaluating the application of NK-cells expanded ex-vivo and pre-treated with CHIR99021 in patients with AML (NCT03081780), ovarian cancer (NCT03213964) and other solid tumors (NCT03319459) Phase 2 trial of LY2090314 and Chemotherapy in Participants With Metastatic Pancreatic Cancer (NCT01632306) | |
ROS | Superoxide dismutase and other SOD-mimicking substances partially restore the NK-cell mediated killing of YAC-1 cells inhibited by superoxide [253]. | None |
Histamine reverses granulocyte-induced inhibition of human NK-cell mediated killing of K562 cells [254]. Serotonin restores NK cell-mediated killing of K562 cells inhibited by mononuclear phagocytes [255] | Maintenance Therapy With Ceplene® (Histamine) and IL-2 on Immune Response and MRD in Acute Myeloid Leukemia NCT01347996 -A Study of HDC/IL-2 Treatment in Chronic Myelomonocytic Leukemia (CMML) NCT03040401 | |
Catalase protects human NK cells from H2O2 induced apoptosis [206,253,256]. | None | |
Genetic inhibition of NOX2 (Nox2−/− mice that lack the myeloid gp91phox subunit of NOX2) or NOX2 inhibitor HDC reduces melanoma metastasis in a murine NK cell-dependent model of melanoma metastasis [257]. NOX2 inhibitors HDC and diphenylene iodonium chloride (DPI) play a protective role from monocyte-derived ROS-dependent NK cell apoptosis and mostly restore NK cell-mediated ADCC of primary CLL cells. NOX2 inhibitor HDC promotes degranulation of NK cells toward CMML cells in ADCC process and reverses CMML-induced NK cell apoptosis [208,256,257]. | None | |
ERK1/2 inhibitor PD98059 protects NK cell from H2O2-induced or monocyte-dependent apoptosis [207]. | None | |
TGF-β | Chemical inhibitors- TGF-β receptor kinase inhibitor, galunisertib (LY2157299) improves the activity of NK cells in metastatic colon cancer mouse model [209]. | A Study of Galunisertib on the Immune System in Participants with Cancer NCT02304419 ExIST Study of LY2157299 (Galunisertib) in Rectal Cancer NCT02688712 |
anti-TGF-β antibodies- are shown to restore NK cells degranulation and cytokine release [258]. | -Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma NCT01112293 -Safety and Efficacy Study of GC1008 to Treat Renal Cell Carcinoma or Malignant Melanoma NCT00356460 | |
Genetic modification strategies- TGF-β dominant-negative receptor knockout receptor coupled to NK-activating domains (DAP12 or synNotch-RELA) enhance the cytotoxic activity of NK cells (particularly with DAP12 domain) [259] | None | |
Glutamine depletion | CB-839 It has been reported that glutaminolysis can be inhibited without reducing NK cell functional responses [34]. | Study of the Glutaminase Inhibitor CB-839 in Solid Tumors NCT02071862 |
Tryptophan metabolites | IDO1 inhibition restores NKG2D expression on NK cells and promotes their proliferation [260,261]. IDO pathway inhibition enhances NK cell tumor infiltration and antitumor activity [262]. | -Intraperitoneal Natural Killer Cells and INCB024360 for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer NCT02118285 -NLG802 Indoleamine 2,3-Dioxygenase (IDO) Inhibitor in Advanced Solid Tumors NCT03164603 |
AHR antagonism increases cancer cell susceptibility to NK cell-mediated cytotoxicity and enhances NK cell-mediated ADCC [263]. | -A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients with Advanced Cancer NCT04069026 -IK-175 in Patients with Advanced or Metastatic Solid Tumors and Urothelial Carcinoma NCT04200963 | |
IL-18 treatment reversed IDO-mediated NK cell inhibition by upregulating NKG2D receptor [213]. | None | |
Adenosine | A3R agonists: C1-IB-MECA increases activation and NK cells infiltration of B16-F10 melanoma. CF101 potentiation of NK cells’ activity [264,265,266]. | None |
A2aR antagonists: SCH58261- enhances NK cells maturation, cytokine production, cytotoxic function against tumor cell lines, increases expression of granzyme B and reduces metastasis in a perforin-dependent manner. Increases NK cells infiltration of BRAFV600E-mutant melanoma. Promotes mouse NK cells proliferation and differentiation of human CD56bright into CD56dim mature NK cells. ZM241385- restores the cytotoxic function of IL-2 activated NK cells and cytokines production [267,268,269,270,271,272,273]. | -A Study to Evaluate Immunotherapy Combinations in Participants with Gastrointestinal Malignancies NCT03720678 -A Study to Evaluate the Safety and Tolerability of Immunotherapy Combinations in Participants with Advanced Malignancies NCT03629756 - A Study to Evaluate Safety/Tolerability of Immunotherapy Combinations in Participants with Triple-Negative Breast Cancer or Gynecologic Malignancies NCT03719326 | |
CD73 inhibitor: APCP- reduces metastasis trough decreased A2aR-mediated suppression of NK cell-mediated cytotoxicity. Improves lytic activity of NK cells [270,273]. | A Study of the CD73 Inhibitor LY3475070 Alone or in Combination with Pembrolizumab in Participants with Advanced Cancer NCT04148937 | |
anti-mouse CD73 antibody: TY/23- enhances anti-metastatic activity derived by NK cells [272]. Anti-human CD73 antibody increases the cytotoxicity of NK cells against ovarian cancer cell lines overexpressing CD73 [274]. | A Study of AK119 (Anti-CD73) in Combination with AK104 (PD-1/CTLA-4) in Subjects with Advanced Solid Tumors -Study of GS-1423 (Anti-CD73-TGFβ-Trap Bifunctional Antibody) in Participants with Advanced Solid Tumors NCT03954704 | |
Anti-human CD39 antibody increases the cytotoxicity of NK cells against ovarian cancer cell lines overexpressing CD39 [274]. | - Study of SRF617 (anti-CD39 antibody) in Patients with Advanced Solid Tumors NCT04336098 - TTX-030 (anti-CD39 antibody) Single Agent and in Combination With Immunotherapy or Chemotherapy for Patients With Advanced Cancers NCT03884556 | |
CD39 inhibitors: Polyoxometalate-1 (POM-1)- reverses Treg-mediated suppression of NK cells cytotoxicity and enhances their anti-metastatic activity. ARL67156- enhances the lytic activity of polyclonal NK cells [270,275,276]. | None | |
Arginine | MDSCs upregulate arginase and catabolise arginine to NO. It has been found that NO impairs NK cell antibody-dependent cellular cytotoxicity and that the inhibition of iNOS can rescue this function [277]. | |
Inhibition of the arginase activity by CB-1158 reduces tumor growth and increases tumor-infiltrating NK cells in vitro and in vivo [278]. OATD-02, another arginase inhibitor, has been shown to delay cancer progression [279,280]. | Arginase Inhibitor INCB001158 as a Single Agent and in Combination with Immune Checkpoint Therapy in Patients with Advanced/Metastatic Solid Tumors NCT02903914 | |
Arachidonic acid metabolites | Selective COX-2 inhibitors increase cancer cell sensitivity to NK cell-mediated lysis [281]. | -Perioperative Administration of COX 2 Inhibitors and Beta Blockers to Women Undergoing Breast Cancer Surgery NCT00502684 -Perioperative Intervention to Reduce Metastatic Processes in Pancreatic Cancer Patients Undergoing Curative Surgery (BC-PC) NCT03838029 |
EP2 antagonists restore tumor NK cell-mediated lysis [216]. EP4 antagonists restore NK cell antitumor activity cytokine production and migratory potential. Also, they decrease MHC I expression on cancer cells rendering them more sensitive to NK cell-mediated cytotoxicity [151,226]. | Phase 1a/1b Study of TPST-1495 (EP2/EP4 antagonist) Alone and With Pembrolizumab in Subjects with Solid Tumors |
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Domagala, J.; Lachota, M.; Klopotowska, M.; Graczyk-Jarzynka, A.; Domagala, A.; Zhylko, A.; Soroczynska, K.; Winiarska, M. The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity. Cancers 2020, 12, 3542. https://doi.org/10.3390/cancers12123542
Domagala J, Lachota M, Klopotowska M, Graczyk-Jarzynka A, Domagala A, Zhylko A, Soroczynska K, Winiarska M. The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity. Cancers. 2020; 12(12):3542. https://doi.org/10.3390/cancers12123542
Chicago/Turabian StyleDomagala, Joanna, Mieszko Lachota, Marta Klopotowska, Agnieszka Graczyk-Jarzynka, Antoni Domagala, Andriy Zhylko, Karolina Soroczynska, and Magdalena Winiarska. 2020. "The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity" Cancers 12, no. 12: 3542. https://doi.org/10.3390/cancers12123542