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01-10-2016 | Focussed Research Review

Modulation of innate immunity in the tumor microenvironment

Authors: Elena Gonzalez-Gugel, Mansi Saxena, Nina Bhardwaj

Published in: Cancer Immunology, Immunotherapy | Issue 10/2016

Abstract

A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses. We have investigated innate immune cells (dendritic cells, NK cells) in the tumor microenvironment (TME) in order to devise effective targeted anticancer immune therapies. We find that matrix metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells, cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both these events independently culminate in programing the DCs to promote pro-tumorigenic T_H2 T cell differentiation. In addition, we have shown that NK cells become functionally exhausted in melanoma patients. We identified the expression of Tim-3 as one of the factors responsible for NK cell exhaustion and showed that anti-Tim3 antibodies partially reversed this exhaustion. We have initiated local intervention strategies such as intra-tumoral administration of DC activating Poly-ICLC and compared the efficacy of different TLR agonists and melanoma antigens for use as combination tumor vaccine in clinical trials. Such approaches will provide a unique insight into tumor biology and will facilitate in development of highly effective and cell type-specific immune therapies.

Lauerova L, Dusek L, Simickova M, Kocak I, Vagundova M, Zaloudik J, Kovarik J (2002) Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response. Neoplasma 49(3):159–166PubMed

Dye DE, Medic S, Ziman M, Coombe DR (2013) Melanoma biomolecules: independently identified but functionally intertwined. Front Oncol 3:252. doi:10.3389/fonc.2013.00252 CrossRefPubMedPubMedCentral

Roomi MW, Monterrey JC, Kalinovsky T, Rath M, Niedzwiecki A (2009) Distinct patterns of matrix metalloproteinase-2 and -9 expression in normal human cell lines. Oncol Rep 21(3):821–826PubMed

Oviedo-Orta E, Bermudez-Fajardo A, Karanam S, Benbow U, Newby AC (2008) Comparison of MMP-2 and MMP-9 secretion from T helper 0, 1 and 2 lymphocytes alone and in coculture with macrophages. Immunology 124(1):42–50. doi:10.1111/j.1365-2567.2007.02728.x CrossRefPubMedPubMedCentral

Polette M, Gilbert N, Stas I, Nawrocki B, Noel A, Remacle A et al (1994) Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy. Virchows Arch 424(6):641–645CrossRefPubMed

Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S (1998) Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res 58(5):1048–1051PubMed

Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174. doi:10.1038/nrc745 CrossRefPubMed

Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392. doi:10.1126/science.1067100 CrossRefPubMed

Renaud V, Godefroy E, Larrieu P, Fleury F, Jotereau F, Guilloux Y (2010) Folding of matrix metalloproteinase-2 prevents endogenous generation of MHC class-I restricted epitope. PLoS ONE 5(7):e11894. doi:10.1371/journal.pone.0011894 CrossRefPubMedPubMedCentral

10.

Godefroy E, Moreau-Aubry A, Diez E, Dreno B, Jotereau F, Guilloux Y (2005) alpha v beta3-dependent cross-presentation of matrix metalloproteinase-2 by melanoma cells gives rise to a new tumor antigen. J Exp Med 202(1):61–72. doi:10.1084/jem.20042138 CrossRefPubMedPubMedCentral

11.

Godefroy E, Manches O, Dreno B, Hochman T, Rolnitzky L, Labarriere N et al (2011) Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell 19(3):333–346. doi:10.1016/j.ccr.2011.01.037 CrossRefPubMedPubMedCentral

12.

Croft M, So T, Duan W, Soroosh P (2009) The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev 229(1):173–191. doi:10.1111/j.1600-065X.2009.00766.x CrossRefPubMedPubMedCentral

13.

Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202(9):1213–1223. doi:10.1084/jem.20051135 CrossRefPubMedPubMedCentral

14.

Eisenbarth SC, Piggott DA, Bottomly K (2003) The master regulators of allergic inflammation: dendritic cells in Th2 sensitization. Curr Opin Immunol 15(6):620–626CrossRefPubMed

15.

Godefroy E, Gallois A, Idoyaga J, Merad M, Tung N, Monu N et al (2014) Activation of toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic-cell-mediated inflammatory responses. Cell Rep 9(5):1856–1870. doi:10.1016/j.celrep.2014.10.067 CrossRefPubMedPubMedCentral

16.

Colucci F, Caligiuri MA, Di Santo JP (2003) What does it take to make a natural killer? Nat Rev Immunol 3(5):413–425. doi:10.1038/nri1088 CrossRefPubMed

17.

Jaleco AC, Blom B, Res P, Weijer K, Lanier LL, Phillips JH et al (1997) Fetal liver contains committed NK progenitors, but is not a site for development of CD34 + cells into T cells. J Immunol 159(2):694–702PubMed

18.

Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H et al (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16 + NK-cell subset. Blood 116(19):3865–3874. doi:10.1182/blood-2010-04-282301 CrossRefPubMedPubMedCentral

19.

Eckl J, Buchner A, Prinz PU, Riesenberg R, Siegert SI, Kammerer R et al (2012) Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging. J Mol Med (Berl) 90(1):55–66. doi:10.1007/s00109-011-0806-7 CrossRef

20.

Hsia JY, Chen JT, Chen CY, Hsu CP, Miaw J, Huang YS et al (2005) Prognostic significance of intratumoral natural killer cells in primary resected esophageal squamous cell carcinoma. Chang Gung Med J 28(5):335–340PubMed

21.

Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H et al (2000) Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88(3):577–583CrossRefPubMed

22.

McKay K, Moore PC, Smoller BR, Hiatt KM (2011) Association between natural killer cells and regression in melanocytic lesions. Hum Pathol 42(12):1960–1964. doi:10.1016/j.humpath.2011.02.019 CrossRefPubMed

23.

Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA 97(6):2731–2736. doi:10.1073/pnas.050588297 CrossRefPubMedPubMedCentral

24.

Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562):2097–2100. doi:10.1126/science.1068440 CrossRefPubMed

25.

Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R et al (2005) Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 105(6):2594–2600. doi:10.1182/blood-2004-04-1441 CrossRefPubMed

26.

Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL et al (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331(6013):44–49. doi:10.1126/science.1198687 CrossRefPubMedPubMedCentral

27.

Norris S, Coleman A, Kuri-Cervantes L, Bower M, Nelson M, Goodier MR (2012) PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol 25(4):329–332. doi:10.1089/vim.2011.0096 CrossRefPubMed

28.

Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F et al (2007) Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet 39(6):733–740. doi:10.1038/ng2035 CrossRefPubMedPubMedCentral

29.

Schafer JL, Li H, Evans TI, Estes JD, Reeves RK (2015) Accumulation of cytotoxic CD16 + NK Cells in simian immunodeficiency virus-infected lymph nodes associated with in situ differentiation and functional anergy. J Virol 89(13):6887–6894. doi:10.1128/JVI.00660-15 CrossRefPubMedPubMedCentral

30.

Alter G, Jost S, Rihn S, Reyor LL, Nolan BE, Ghebremichael M et al (2011) Reduced frequencies of NKp30 + NKp46 + , CD161 + , and NKG2D + NK cells in acute HCV infection may predict viral clearance. J Hepatol 55(2):278–288. doi:10.1016/j.jhep.2010.11.030 CrossRefPubMed

31.

Bonorino P, Ramzan M, Camous X, Dufeu-Duchesne T, Thelu MA, Sturm N et al (2009) Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 51(3):458–467. doi:10.1016/j.jhep.2009.05.030 CrossRefPubMed

32.

Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R et al (2011) Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Investig 121(9):3609–3622. doi:10.1172/JCI45816 CrossRefPubMedPubMedCentral

33.

Jewett A, Tseng HC (2011) Tumor induced inactivation of natural killer cell cytotoxic function; implication in growth, expansion and differentiation of cancer stem cells. J Cancer 2:443–457CrossRefPubMedPubMedCentral

34.

Gill S, Vasey AE, De Souza A, Baker J, Smith AT, Kohrt HE et al (2012) Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. Blood 119(24):5758–5768. doi:10.1182/blood-2012-03-415364 CrossRefPubMedPubMedCentral

35.

da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK et al (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2(5):410–422. doi:10.1158/2326-6066.CIR-13-0171 CrossRefPubMedPubMedCentral

36.

Gallois A, Silva I, Osman I, Bhardwaj N (2014) Reversal of natural killer cell exhaustion by TIM-3 blockade. Oncoimmunology 3(12):e946365. doi:10.4161/21624011.2014.946365 CrossRefPubMedPubMedCentral

37.

Wherry EJ (2011) T cell exhaustion. Nat Immunol 12(6):492–499CrossRefPubMed

38.

Yi JS, Cox MA, Zajac AJ (2010) T-cell exhaustion: characteristics, causes and conversion. Immunology 129(4):474–481. doi:10.1111/j.1365-2567.2010.03255.x CrossRefPubMedPubMedCentral

39.

Huang YH, Zhu C, Kondo Y, Anderson AC, Gandhi A, Russell A et al (2015) CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517(7534):386–390. doi:10.1038/nature13848 CrossRefPubMed

40.

Chan CJ, Martinet L, Gilfillan S, Souza-Fonseca-Guimaraes F, Chow MT, Town L et al (2014) The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat Immunol 15(5):431–438. doi:10.1038/ni.2850 CrossRefPubMed

41.

Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Demoulins T et al (2014) Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance. J Clin Investig 124(4):1810–1820. doi:10.1172/JCI65899 CrossRefPubMedPubMedCentral

42.

Dhodapkar MV, Steinman RM, Sapp M, Desai H, Fossella C, Krasovsky J et al (1999) Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J Clin Investig 104(2):173–180. doi:10.1172/JCI6909 CrossRefPubMedPubMedCentral

43.

Dhodapkar MV, Krasovsky J, Steinman RM, Bhardwaj N (2000) Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes. J Clin Investig 105(6):R9–R14. doi:10.1172/JCI9051 CrossRefPubMedPubMedCentral

44.

Adams S, O’Neill DW, Nonaka D, Hardin E, Chiriboga L, Siu K et al (2008) Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant. J Immunol 181(1):776–784CrossRefPubMedPubMedCentral

45.

Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O’Neill D et al (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 104(21):8947–8952. doi:10.1073/pnas.0703395104 CrossRefPubMedPubMedCentral

46.

Sabado RL, Pavlick A, Gnjatic S, Cruz CM, Vengco I, Hasan F et al (2015) Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma. Cancer Immunol Res 3(3):278–287. doi:10.1158/2326-6066.CIR-14-0202 CrossRefPubMedPubMedCentral

47.

Salazar AM, Erlich RB, Mark A, Bhardwaj N, Herberman RB (2014) Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial. Cancer Immunol Res 2(8):720–724. doi:10.1158/2326-6066.CIR-14-0024 CrossRefPubMed

Title: Modulation of innate immunity in the tumor microenvironment
Authors: Elena Gonzalez-Gugel
Mansi Saxena
Nina Bhardwaj
Publication date: 01-10-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 10/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-016-1859-9

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