IL-36 Signaling in the Tumor Microenvironment

  • Manoj Chelvanambi
  • Aliyah M. Weinstein
  • Walter J. StorkusEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1240)


The ability of the immune system to prevent or control the growth of tumor cells is critically dependent on inflammatory processes that lead to the activation, expansion, and recruitment of antitumor effector cells into the tumor microenvironment (TME). These processes are orchestrated by soluble cytokines produced in tissues that alarm local immune surveillance cells (such as dendritic cells, DCs) to mobilize protective antitumor immune populations (B cells, T cells). The interleukin (IL)-36 family of pro-inflammatory cytokines plays an important role in multiple disease processes, ranging from an instigator of autoimmune psoriasis to an initiator of therapeutic immune responses against tumor cells. This chapter will focus on the biologic role of immunomodulatory IL-36 family cytokines in the cancer setting and their potential utility in the design of effective interventional therapies. (127 words)


Cancer Cytokine Dendritic cells IL-1 IL-36 Immunotherapy Inflammation Interleukin T cells Tertiary lymphoid structures Tumor Tumor microenvironment 


  1. 1.
    Ainscough JS, Macleod T, McGonagle D, Brakefield R, Baron JM, Alase A et al (2017) Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36gamma. Proc Natl Acad Sci U S A 114(13):E2748–E2757. Scholar
  2. 2.
    Atkins E (1984) Fever: the old and the new. J Infect Dis 149(3):339–348. Scholar
  3. 3.
    Bachmann M, Scheiermann P, Hardle L, Pfeilschifter J, Muhl H (2012) IL-36gamma/IL-1F9, an innate T-bet target in myeloid cells. J Biol Chem 287(50):41684–41696. Scholar
  4. 4.
    Barton SP, Abdullah MS, Marks R (1992) Quantification of microvascular changes in the skin in patients with psoriasis. Br J Dermatol 126(6):569–574. Scholar
  5. 5.
    Beeson PB (1948) Temperature-elevating effect of a substance obtained from polymorphonuclear leucocytes. J Clin Invest 27(4):524PubMedGoogle Scholar
  6. 6.
    Borst J, Ahrends T, Babala N, Melief CJM, Kastenmuller W (2018) CD4(+) T cell help in cancer immunology and immunotherapy. Nat Rev Immunol 18(10):635–647. Scholar
  7. 7.
    Bridgewood C, Stacey M, Alase A, Lagos D, Graham A, Wittmann M (2017) IL-36gamma has proinflammatory effects on human endothelial cells. Exp Dermatol 26(5):402–408. Scholar
  8. 8.
    Bull RH, Bates DO, Mortimer PS (1992) Intravital video-capillaroscopy for the study of the microcirculation in psoriasis. Br J Dermatol 126(5):436–445. Scholar
  9. 9.
    Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL et al (1998) MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 273(20):12203–12209. Scholar
  10. 10.
    Busfield SJ, Comrack CA, Yu G, Chickering TW, Smutko JS, Zhou H et al (2000) Identification and gene organization of three novel members of the IL-1 family on human chromosome 2. Genomics 66(2):213–216. Scholar
  11. 11.
    Chang J, Burkett PR, Borges CM, Kuchroo VK, Turka LA, Chang CH (2013) MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling. Proc Natl Acad Sci U S A 110(6):2270–2275. Scholar
  12. 12.
    Chen L, Taylor JL, Sabins NC, Lowe DB, Qu Y, You Z, Storkus WJ (2013) Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells. Cancer Gene Ther 20(8):469–477. Scholar
  13. 13.
    Chi H-H, Hua K-F, Lin Y-C, Chu C-L, Hsieh C-Y, Hsu Y-J et al (2017) IL-36 signaling facilitates activation of the NLRP3 inflammasome and IL-23/IL-17 axis in renal inflammation and fibrosis. J Am Soc Nephrol 28(7):2022–2037. Scholar
  14. 14.
    Clancy DM, Sullivan GP, Moran HBT, Henry CM, Reeves EP, McElvaney NG et al (2018) Extracellular neutrophil proteases are efficient regulators of IL-1, IL-33, and IL-36 cytokine activity but poor effectors of microbial killing. Cell Rep 22(11):2937–2950. Scholar
  15. 15.
    Costelloe C, Watson M, Murphy A, McQuillan K, Loscher C, Armstrong ME et al (2008) IL-1F5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8. J Neurochem 105(5):1960–1969. Scholar
  16. 16.
    Creamer D, Allen MH, Sousa A, Poston R, Barker JN (1997) Localization of endothelial proliferation and microvascular expansion in active plaque psoriasis. Br J Dermatol 136(6):859–865CrossRefGoogle Scholar
  17. 17.
    Curtis BM, Widmer MB, deRoos P, Qwarnstrom EE (1990) IL-1 and its receptor are translocated to the nucleus. J Immunol 144(4):1295–1303PubMedGoogle Scholar
  18. 18.
    Dalod M, Chelbi R, Malissen B, Lawrence T (2014) Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming. EMBO J 33(10):1104–1116. Scholar
  19. 19.
    Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S et al (2001) Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol 167(3):1440–1446. Scholar
  20. 20.
    Dietrich D, Martin P, Flacher V, Sun Y, Jarrossay D, Brembilla N et al (2016) Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines. Cytokine 84:88–98. Scholar
  21. 21.
    Dinarello CA (2010) IL-1: discoveries, controversies and future directions. Eur J Immunol 40(3):599–606. Scholar
  22. 22.
    Foster AM, Baliwag J, Chen CS, Guzman AM, Stoll SW, Gudjonsson JE et al (2014) IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. J Immunol 192(12):6053–6061. Scholar
  23. 23.
    Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39(6):1003–1018. Scholar
  24. 24.
    Goc J, Germain C, Vo-Bourgais TKD, Lupo A, Klein C, Knockaert S et al (2014) Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8<sup>+</sup> T cells. Cancer Res 74(3):705–715. Scholar
  25. 25.
    Griffioen AW, Damen CA, Blijham GH, Groenewegen G (1996a) Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood 88(2):667–673CrossRefGoogle Scholar
  26. 26.
    Griffioen AW, Damen CA, Martinotti S, Blijham GH, Groenewegen G (1996b) Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: the role of angiogenic factors. Cancer Res 56(5):1111–1117PubMedGoogle Scholar
  27. 27.
    Guo J, Tu J, Hu Y, Song G, Yin Z (2019) Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis. Drug Des Devel Ther 13:581–588. Scholar
  28. 28.
    Henry CM, Sullivan GP, Clancy DM, Afonina IS, Kulms D, Martin SJ (2016) Neutrophil-derived proteases escalate inflammation through activation of IL-36 family cytokines. Cell Rep 14(4):708–722. Scholar
  29. 29.
    Hewitt SL, Bai A, Bailey D, Ichikawa K, Zielinski J, Karp R et al (2019) Durable anticancer immunity from intratumoral administration of IL-23, IL-36gamma, and OX40L mRNAs. Sci Transl Med 11(477):eaat9143. Scholar
  30. 30.
    Hiraoka N, Ino Y, Yamazaki-Itoh R (2016) Tertiary lymphoid organs in cancer tissues. Front Immunol 7:244. Scholar
  31. 31.
    Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Vaitkiene S, Sakalauskas R (2018) Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer. BMC Immunol 19(1):3. Scholar
  32. 32.
    Li C, Zienkiewicz J, Hawiger J (2005) Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway. J Biol Chem 280(28):26152–26159. Scholar
  33. 33.
    Li N, Yamasaki K, Saito R, Fukushi-Takahashi S, Shimada-Omori R, Asano M, Aiba S (2014) Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36gamma induction in human epidermal keratinocytes. J Immunol 193(10):5140–5148. Scholar
  34. 34.
    Lian LH, Milora KA, Manupipatpong KK, Jensen LE (2012) The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36gamma. J Invest Dermatol 132(5):1346–1353. Scholar
  35. 35.
    Macleod T, Doble R, McGonagle D, Wasson CW, Alase A, Stacey M, Wittmann M (2016) Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 receptor antagonist. Sci Rep 6:24880. Scholar
  36. 36.
    Milora KA, Fu H, Dubaz O, Jensen LE (2015) Unprocessed interleukin-36alpha regulates psoriasis-like skin inflammation in cooperation with interleukin-1. J Invest Dermatol 135(12):2992–3000. Scholar
  37. 37.
    Mosley B, Urdal DL, Prickett KS, Larsen A, Cosman D, Conlon PJ et al (1987) The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor. J Biol Chem 262(7):2941–2944PubMedGoogle Scholar
  38. 38.
    Moussion C, Ortega N, Girard JP (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’. PLoS One 3(10):e3331. Scholar
  39. 39.
    Müller A, Hennig A, Lorscheid S, Grondona P, Schulze-Osthoff K, Hailfinger S, Kramer D (2018) IκBζ is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes. Proc Natl Acad Sci U S A 115(40):10088–10093. Scholar
  40. 40.
    Mutamba S, Allison A, Mahida Y, Barrow P, Foster N (2012) Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9. Eur J Immunol 42(3):607–617. Scholar
  41. 41.
    Nanjappa SG, Hernandez-Santos N, Galles K, Wuthrich M, Suresh M, Klein BS (2015) Intrinsic MyD88-Akt1-mTOR signaling coordinates disparate Tc17 and Tc1 responses during vaccine immunity against fungal pneumonia. PLoS Pathog 11(9):e1005161. Scholar
  42. 42.
    Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V et al (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 89(3):432–437. Scholar
  43. 43.
    Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6(7):541–550. Scholar
  44. 44.
    Renert-Yuval Y, Horev L, Babay S, Tams S, Ramot Y, Zlotogorski A, Molho-Pessach V (2014) IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient. Int J Dermatol 53(7):866–868. Scholar
  45. 45.
    Rider P, Kaplanov I, Romzova M, Bernardis L, Braiman A, Voronov E, Apte RN (2012) The transcription of the alarmin cytokine interleukin-1 alpha is controlled by hypoxia inducible factors 1 and 2 alpha in hypoxic cells. Front Immunol 3:290. Scholar
  46. 46.
    Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB et al (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849. Scholar
  47. 47.
    Sautes-Fridman C, Petitprez F, Calderaro J, Fridman WH (2019) Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 19(6):307–325. Scholar
  48. 48.
    Scheibe K, Backert I, Wirtz S, Hueber A, Schett G, Vieth M et al (2017) IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo. Gut 66(5):823–838. Scholar
  49. 49.
    Scheiermann P, Bachmann M, Härdle L, Pleli T, Piiper A, Zwissler B et al (2015) Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury. Sci Rep 5:8521. Scholar
  50. 50.
    Schmid MC, Varner JA (2010) Myeloid cells in the tumor microenvironment: modulation of tumor angiogenesis and tumor inflammation. J Oncol 2010:201026. Scholar
  51. 51.
    Smith DE, Renshaw BR, Ketchem RR, Kubin M, Garka KE, Sims JE (2000) Four new members expand the interleukin-1 superfamily. J Biol Chem 275(2):1169–1175. Scholar
  52. 52.
    Solahaye-Kahnamouii S, Farhadi F, Rahkare-Farshi M, Pakdel F, Kashefimehr A, Pouralibaba F et al (2014) The effect of interleukin 36 gene therapy in the regression of tumor. Iran J Cancer Prev 7(4):197–203PubMedPubMedCentralGoogle Scholar
  53. 53.
    Sullivan GP, Henry CM, Clancy DM, Mametnabiev T, Belotcerkovskaya E, Davidovich P et al (2018) Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases. Cell Death Dis 9(3):378. Scholar
  54. 54.
    Swindell WR, Beamer MA, Sarkar MK, Loftus S, Fullmer J, Xing X et al (2018) RNA-Seq analysis of IL-1B and IL-36 responses in epidermal keratinocytes identifies a shared MyD88-dependent gene signature. Front Immunol 9:80. Scholar
  55. 55.
    Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE (2004) Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem 279(14):13677–13688. Scholar
  56. 56.
    Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, Sims JE (2011) Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. J Biol Chem 286(49):42594–42602. Scholar
  57. 57.
    Tsurutani N, Mittal P, St Rose MC, Ngoi SM, Svedova J, Menoret A et al (2016) Costimulation endows immunotherapeutic CD8 T cells with IL-36 responsiveness during aerobic glycolysis. J Immunol 196(1):124–134. Scholar
  58. 58.
    Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. Scholar
  59. 59.
    Vigne S, Palmer G, Lamacchia C, Martin P, Talabot-Ayer D, Rodriguez E et al (2011) IL-36R ligands are potent regulators of dendritic and T cells. Blood 118(22):5813–5823. Scholar
  60. 60.
    Vigne S, Palmer G, Martin P, Lamacchia C, Strebel D, Rodriguez E et al (2012) IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells. Blood 120(17):3478–3487. Scholar
  61. 61.
    Wang W, Yu X, Wu C, Jin H (2017) IL-36γ inhibits differentiation and induces inflammation of keratinocyte via Wnt signaling pathway in psoriasis. Int J Med Sci 14(10):1002–1007. Scholar
  62. 62.
    Wang X, Zhao X, Feng C, Weinstein A, Xia R, Wen W et al (2015) IL-36gamma transforms the tumor microenvironment and promotes type 1 lymphocyte-mediated antitumor immune responses. Cancer Cell 28(3):296–306. Scholar
  63. 63.
    Weinstein AM, Chen L, Brzana EA, Patil PR, Taylor JL, Fabian KL et al (2017) Tbet and IL-36gamma cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment. Oncoimmunology 6(6):e1322238. Scholar
  64. 64.
    Weinstein AM, Giraldo NA, Petitprez F, Julie C, Lacroix L, Peschaud F et al (2019) Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer. Cancer Immunol Immunother 68(1):109–120. Scholar
  65. 65.
    Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, Di W (2014a) A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res 7:19. Scholar
  66. 66.
    Zhang Y, Zhang Y, Gu W, Sun B (2014b) TH1/TH2 cell differentiation and molecular signals. Adv Exp Med Biol 841:15–44. Scholar
  67. 67.
    Zhao X, Chen X, Shen X, Tang P, Chen C, Zhu Q et al (2019) IL-36β promotes CD8+ T cell activation and antitumor immune responses by activating mTORC1. Front Immunol 10(1803).
  68. 68.
    Zhu J, Jankovic D, Oler AJ, Wei G, Sharma S, Hu G et al (2012) The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity 37(4):660–673. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Manoj Chelvanambi
    • 1
  • Aliyah M. Weinstein
    • 1
  • Walter J. Storkus
    • 1
    • 2
    Email author
  1. 1.Departments of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Departments of DermatologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations