Non-effector Cell Pathways
- PD-1 Pathway
- CTLA-4 Pathway
- Additional Effector T-Cell
- SLAMF7 Pathway
- Additional NK Cell
- Non-effector Cell
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.1* Tregs act to limit the immune response, and the release of adenosine helps Tregs shut down immune activity.2,3
Cancer exploits the function of CD73 to reduce antitumor immunity. Like Tregs, tumor cells express CD73 and release adenosine into the tumor microenvironment.4-6 In cellular studies, adenosine powerfully inhibits the antitumor immune response, including proliferation and production of cytokines.1
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.7
*CD39 catalyzes ATP or ADP into AMP, which is then converted by CD73 to adenosine, which may mediate immunosuppressive effects on T cells.
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.1
In the tumor microenvironment, some macrophages evolve from antitumor to protumor in their activity.2 These are called tumor-associated macrophages (TAMs). Through the secretion of certain immunosuppressive factors (eg, cytokines, chemokines, and enzymes), TAMs promote cancer survival and drive immunosuppression, supporting tumor growth.2
CSF1, the ligand for CSF1R, is a dominant regulator of macrophage differentiation and function.3 In cancer patients, high CSF1 concentrations are associated with poorer prognosis.3,4 Mouse models have shown that tumor cells use CSF1 to target CSF1R on macrophages, stimulating the development and survival of TAMs.5
In preclinical studies, blockade of CSF1R—depriving CSF1 of its target receptor—resulted in depletion of TAMs and improved T-cell responses.6,7
EP4: promotes development of immunosuppressive cells
Prostaglandin E receptor 4 (EP4) is a prostanoid receptor expressed by myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), dendritic cells (DCs), CD8+ effector T cells, natural killer (NK) cells, and other immune cells.1-6 EP4 is a G-protein coupled receptor; on engagement with its ligand, prostaglandin E2 (PGE2), and subsequent signal transduction, EP4 mediates suppression of both innate and adaptive immune functions (eg, increased infiltration of immunosuppressive cells, such as MDSCs and TAMs, and suppression of immune effector cells, such as CD8+ T cells and NK cells).
Cancer cells can secrete PGE2, which creates an immunosuppressive environment and promotes tumor progression.3,7-9 In addition, the interaction of PGE2 with EP4 has been implicated in promoting Treg development.7
Preclinical evidence suggests that blocking PGE2 signaling through EP4 receptors leads to a decrease in the abundance of MDSCs/TAMs and an increase in cytotoxic T-cell and NK activity.1-4
IDO1: metabolizes cellular fuel to drive immune suppression
Indoleamine 2,3-dioxygenase-1 (IDO1) is an enzyme expressed in antigen-presenting cells (APCs).1,2 Metabolic enzymes, such as IDO1, require activation by a cofactor.3 The activation of IDO1 is determined by the dynamic binding of its cofactor.4 When bound, activated IDO1 metabolizes tryptophan, an amino acid necessary for cell survival, into immunosuppressive kynurenine.1,5 Normally, the production of immunosuppressive kynurenine acts as a counterbalance to prevent overactivation of the immune response.2,6,7
Tumors can hijack this immunosuppressive process. They evolve to increase IDO1 expression in both tumor cells and APCs.1,8-10 Upregulation of IDO1 depletes tryptophan and generates elevated levels of kynurenine.11 This suppresses T-cell proliferation and promotes regulatory T cell (Treg) development, which helps tumor cells survive.14-19 In a wide variety of solid tumors and hematologic malignancies, increased IDO1 expression is associated with poorer prognosis and outcomes.14-19
As shown in preclinical studies, the inhibition of IDO1 can reduce the number of immunosuppressive Tregs and restore cytotoxic T-cell function.13,20 Furthermore, preclinical data suggest that inhibition of both IDO1 and an immune checkpoint pathway may synergistically improve T-cell proliferation and reduce Treg accumulation.13
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.1 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).2,3 During the normal healing process, IL-8 also activates the angiogenic response to generate new blood vessels.4
Both tumor and tumor-associated stromal cells can upregulate production of IL-8.2,4-8 Tumor-derived IL-8 can cause MDSCs to migrate to the tumor microenvironment, where they suppress the antitumor immune response and expand the stroma.4,7 Tumors can use the stroma as a barrier to prevent immune recognition and subsequent T-cell infiltration.8-10 In addition, tumor-derived IL-8 acts as a potent factor that promotes both angiogenesis and tumor metastasis.4,11
Elevated levels of IL-8 are associated with poorer prognosis in a wide range of tumor types.12,13
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.2,11,14
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.1 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.2,3
NLRP3 expression is first induced by inflammatory signals.4 Subsequently, factors released during tumor cell death, such as adenosine triphosphate (ATP), activate NLRP3 to catalyze the assembly of the NLRP3 inflammasome.3,5 Once assembled, the inflammasome converts inactive IL-1β and IL-18 into their mature, active forms.6 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.2,3,7-10 As the expression and activation of NLRP3 require 2 separate inflammatory signals, full activation of the inflammasome may be restricted to sites of inflammation. This may help avoid damage to healthy cells.11,12
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.2,3,13
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.1,2 STING serves as an innate immune activator that stimulates APCs to drive cytotoxic T-cell activity.2
STING is triggered when an intracellular-sensing protein detects DNA from pathogens or dying tumor cells.3,4 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.3,5 IFNs promote tumor inflammation.6,7 They can stimulate APCs to activate T cells, initiating T-cell proliferation and trafficking to the tumor microenvironment.4,8 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.2,9,10 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.11
Reduced expression of STING may be associated with increased metastasis of tumor cells.12-14 Preclinical data suggest that activation of STING can increase priming of T cells, leading to increased T-cell activation and an inflamed tumor microenvironment.4,6-8 Furthermore, mouse models indicate that activation of STING during simultaneous blockade of immune checkpoint receptors may synergistically promote the antitumor immune response.15,16
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.1,2 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).2,4 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.2,5,6
In the tumor microenvironment, TGFR-TGFβ signaling can promote the development of Tregs, altering the balance between Tregs and cytotoxic T cells.1,2 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.1,7-9 The TGFR-TGFβ interaction can also promote tumor cell invasion and metastasis.10
In multiple tumor types, elevated levels of TGFβ have been associated with a poorer prognosis.11
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.2
Research to further understand these pathways is ongoing.
References – CCR2/CCR5
- Huang B, Lei Z, Zhao J, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 2007;252(1):86-92.
- Weitzenfeld P, Ben-Baruch A. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. 2014;352(1):36-53.
- de Oliveira CEC, Oda JMM, Guembarovski RL, et al. CC chemokine receptor 5: the interface of host immunity and cancer. Dis Markers. 2014;2014:126954. doi:10.1155/2014/126954.
- Lesokhin AM, Hohl TM, Kitano S, et al. Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. 2012;72(4):876-886.
- Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol. 2008;180(1):122-129.
- Mack M, Cihak J, Simonis C, et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J Immunol. 2001;166(7):4697-4704.
- Sica A, Saccani A, Bottazzi B, et al. Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. J Immunol. 2000;164(2):733-738.
- Umansky V, Blattner C, Gebhardt C, Utikal J. CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma. Cancer Immunol Immunother. 2017;66(8):1015-1023.
- Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016;7(19):28697-28710.
- Chang L-Y, Lin Y-C, Mahalingam J, et al. Tumor-derived chemokine CCL5 enhances TGF-β-mediated killing of CD8+ T cells in colon cancer by T-regulatory cells. Cancer Res. 2012;72(5):1092-1102.
- Sanford DE, Belt BA, Panni RZ, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19(13):3404-3415.
- Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344(6186):921-925.
- Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia. 2007;9(7):556-562.
- Wolf MJ, Hoos A, Bauer J, et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell. 2012;22(1):91-105.
- Tan MCB, Goedegebuure PS, Belt BA, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009;182(3):1746-1755.
- Kitamura T, Qian B-Z, Soong D, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015;212(7):1043-1059.
- Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11(6):e0158156.
References – CD73
- Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol. 2006;177(10):6780-6786.
- Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257-1265.
- Picher M, Burch LH, Hirsh AJ, Spychala J, Boucher RC. Ecto 5'-nucleotidase and nonspecific alkaline phosphatase. J Biol Chem. 2003;278(15):13468-13479.
- Häusler SF, del Barrio IM, Strohschein J, et al. Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother. 2011;60(10):1405-1418.
- Serra S, Horenstein AL, Vaisitti T, et al. CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood. 2011;118(23):6141-6152.
- Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103(35):13132-13137.
- Stagg J, Divisekera U, McLaughlin N, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci USA. 2010;107(4):1547-1552.
References – CSF1R
- Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6(6):a021857.
- Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49-61.
- Richardsen E, Uglehus RD, Johnsen SH, Busund LT. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 2015;35(2):865-874.
- Yang L, Wu Q, Xu L, et al. Increased expression of colony stimulating factor-1 is a predictor of poor prognosis in patients with clear-cell renal cell carcinoma. BMC Cancer. 2015. doi:10.1186/s12885-015-1076-5.
- Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models Cancer Res. 2014;74(18):5057-5069.
- Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25(6):846-859.
- Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2012;73(3):1128-1141.
References – IDO1
- Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20(10):469-473.
- Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774.
- Oda S, Sugimoto H, Yoshida T, Shiro Y. Crystallization and preliminary crystallographic studies of human indoleamine 2,3-dioxygenase. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2006;62(Pt 3):221-223.
- Thomas SR, Salahifar H, Mashima R, Hunt NH, Richardson DR, Stocker R. Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-γ-activated human macrophages: posttranslational regulation by pyrrolidine dithiocarbamate. J Immunol. 2001;166(10):6332-6340.
- Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72(21):5435-5440.
- Routy JP, Routy B, Graziani GM, Mehraj V. The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer: implications for immunotherapy. Int J Tryptophan Res. 2016;9:67-77.
- Mbongue JC, Nicholas DA, Torrez TW, Kim N-S, Firek AF, Langridge WHR. The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines (Basel). 2015;3(3):703-729.
- Munn DH, Sharma MD, Hou D, et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest. 2004;114(2):280-290.
- Liu P, Xie B-L, Cai S-H, et al. Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes. BMC Cancer. 2009. doi:10.1186/1471-2407-9-416.
- Löb S, Königsrainer A, Zieker D, et al. IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunol Immunother. 2009;58(1):153-157.
- Chen PW, Mellon JK, Mayhew E, et al. Uveal melanoma expression of indoleamine 2,3-deoxygenase: establishment of an immune privileged environment by tryptophan depletion. Exp Eye Res. 2007;85(5):617-625.
- Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297(5588):1867-1870.
- Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210(7):1389-1402.
- Wainwright DA, Balyasnikova IV, Chang AL, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18(22):6110-6121.
- Folgiero V, Goffredo BM, Filippini P, et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia. Oncotarget. 2014;5(8):2052-2064.
- Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011;17(22):6985-6991.
- Jia Y, Wang H, Wang Y, et al. Low expression of Bin1, along with high expression of IDO in tumor tissue and draining lymph nodes, are predictors of poor prognosis for esophageal squamous cell cancer patients. Int J Cancer. 2015;137(5):1095-1106.
- Mangaonkar A, Mondal AK, Fulzule S, et al. A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression. Sci Rep. 2017;7(1):12892.
- Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51.
- Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269-1274.
References – IL-8
- Duque GA and Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491.
- Alfaro C, Teijeira A, Oñate C, et al. Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res. 2016;22(15):3924-3936.
- Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735-6741.
- David JM, Dominguez C, Hamilton DH, Palena C. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel). 2016;4(3). doi:10.3390/vaccines4030022.
- Katanov C, Lerrer S, Liubomirski Y, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway. Stem Cell Res Ther. 2015;6:87. doi:10.1186/s13287-015-0080-7.
- Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Adenan NAM, Chung I. Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. PLoS ONE. 2013;8(7):e68923.
- Asfaha S, Dubeykovskiy AN, Tomita H, et al. Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis. Gastroenterology. 2013;144(1):155-166.
- Ochsenbein AF, Klenerman P, Karrer U, et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci USA. 1999;96(5):2233-2238.
- Salmon H, Donnadieu E. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix. Oncoimmunology. 2012;1(6):992-994.
- Spiotto MT, Yu P, Rowley DA, et al. Increasing tumor antigen expression overcomes “ignorance” to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity. 2002;17(6):737-747.
- Huang S, Mills L, Mian B, et al. Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol. 2002;161(1):125-134.
- Fujita Y, Okamoto M, Goda H, et al. Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma. PLoS ONE. 2014;9(12):e110378.
- Sanmamed MF, Carranza-Rua O, Alfaro C, et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014;20(22):5697-5707.
- Wu S, Shang H, Cui L, et al. Targeted blockade of interleukin-8 abrogates its promotion of cervical cancer growth and metastasis. Mol Cell Biochem. 2013;375(1-2):69-79.
References – NLRP3
- Guarda G, Zenger M, Yazdi AS, et al. Differential expression of NLRP3 among hematopoietic cells. J Immunol. 2011;186(4):2529-2534.
- Dupaul-Chicoine J, Arabzadeh A, Dagenais M, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity. 2015;43(4):751-763.
- Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170-1178.
- Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262.
- Chow MT, Möller A, Smyth MJ. Inflammation and immune surveillance in cancer. Semin Cancer Biol. 2012;22(1):23-32.
- He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021.
- Ben-Sasson SZ, Hogg A, Hu-li J, et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med. 2013;210(3):491-502.
- Maltez VI, Tubbs AL, Cook KD, et al. Inflammasomes coordinate pyroptosis and natural killer cell cytotoxicity to clear infection by a ubiquitous environmental bacterium. Immunity. 2015;43(5):987-997.
- Embry CA, Franchi L, Nuñez G, Mitchell TC. Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci Signal. 2011;4(171):ra28.
- Freeman BE, Hammarlund E, Raué H-P, Slifka MK. Regulation of innate CD8+ T-cell activation mediated by cytokines. Proc Natl Acad Sci. 2012;109(25):9971-9976.
- Cooper MA, Fehniger TA, Ponnappan A, et al. Interleukin‐1β costimulates interferon‐γ production by human natural killer cells. Eur J Immunol. 2001;31(3):792-801.
- Sharma D, Kanneganti T-D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J Cell Biol. 2016;213(6):617-629.
- Chow MT, Sceneay J, Paget C, et al. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 2012;72(22):5721-5732.
References – STING
- Barber GN. STING-dependent cytosolic DNA sensing pathways. Trends Immunol. 2014;35(2):88-93.
- Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF. The host STING pathway at the interface of cancer and immunity. J Clin Invest. 2016;126(7):2404-2411.
- Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin Cancer Res. 2015;21(21):4774-4779.
- Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842
- Curran E, Chen X, Corrales L, et al. STING pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 2016;15(11):2357-2366.
- Corrales L, Glickman LH, McWhirter SM, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11(7):1018-1830.
- Woo S-R, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 2015;36(4):250-256.
- Ohkuri T, Ghosh A, Kosaka A, et al. STING contributes to anti-glioma immunity via triggering type-I IFN signals in the tumor microenvironment. Cancer Immunol Res. 2014;2(12):1199-1208.
- Swann JB, Hayakawa Y, Zerafa N, et al. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J Immunol. 2007;178(12):7540-7549.
- Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15(7):405-414.
- Gaidt MM, Ebert TS, Chauhan D, et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell. 2017;171(5):1110-1124.
- Song S, Peng P, Tang Z, et al. Decreased expression of STING predicts poor prognosis in patients with gastric cancer. Sci Rep. 2017;7:39858.
- Xia T, Konno H, Ahn J, Barber GN. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 2016;14(2):282-297.
- Xia T, Konno H, Barber GN. Recurrent loss of STING signaling in melanoma correlates with susceptibility to viral oncolysis. Cancer Res. 2016;76(22):6747-6759.
- Demaria O, De Gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408-15413.
- Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med. 2015;7(283):283ra52.
References – TGFR
- Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer. 2013;13(11):788-799.
- Zhong Z, Carroll KD, Policarpio D, et al. Anti-transforming growth factor β receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells. Clin Cancer Res. 2010;16(4):1191-1205.
- Principe DR, Doll JA, Bauer J, et al. TGF-β: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106(2):djt369.
- Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin C-H. Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-β. J Biol Chem. 1994;269(31):20172-20178.
- Yu PF, Huang Y, Xu CL, et al. Downregulation of CXCL12 in mesenchymal stromal cells by TGFβ promotes breast cancer metastasis. Oncogene. 2017;36(6):840-849.
- Letterio JJ, Roberts AB. Regulation of immune responses by TGF-β. Annu Rev Immunol. 1998;16:137-161.
- Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015;147:22-31.
- Wilson EB, El-Jawhari JJ, Neilson AL, et al. Human tumour immune evasion via TGF-β blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity. PLoS ONE. 2011;6(9):e22842.
- Worthington JJ, Fenton TM, Czajkowska BI, Klementowicz JE, Travis MA. Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology. 2012;217(12):1259-1265.
- Padua D, Massagué J. Roles of TGFβ in metastasis. Cell Res. 2009;19(1):89-102.
- Gordon KJ, Blobe GC. Role of transforming growth factor-β superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782(4):197-228.
References – EP4
- Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004;103(2):147-166.
- Majumder M, Xin X, Liu L, Girish GV, Lala PK. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Sci. 2014;105(9):1142-1151.
- Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007;67(9):4507-4513.
- Holt D, Ma X, Kundu N, Fulton A. Prostaglandin E2 (PGE2) suppresses Natural Killer cell function primarily through the PGE2 receptor EP4. Cancer Immunol Immunother. 2011;60(11):1577-1586.
- Chou JP, Ramirez CM, Ryba DM, Koduri MP, Effros RB. Prostaglandin E2 promotes features of replicative senescence in chronically activated human CD8+ T cells. PLoS One. 2014;9(6):e99432.
- Legler DF, Krause P, Scandella E, Singer E, Groettrup M. Prostaglandin E2 is generally required for human dendritic cell migration and exerts its effect via EP2 and EP4 receptors. The Journal of Immunology. 2006;176(2):966-73.
- Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188(1):21-28.
- Rong Y, Yuan CH, Qu Z, et al. Doxorubicin resistant cancer cells activate myeloid-derived suppressor cells by releasing PGE2. Sci Rep. 2016;6:23824. doi:10.1038/srep23824.
- Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118(20):5498-5505.