Skip to main content


Log in

IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript


Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


Arg 1:

Arginase 1


Carboxyfluorescein succinimidyl ester


Epidermal growth factor


Granzyme B




Myeloid-derived suppressor cells


Nitric oxide synthase 2




Tumor-associated macrophages

Tfh cells:

T follicular helper cells

Treg cell:

Regulatory T cell


Vascular endothelial growth factor


  1. Zitvogel L, Tesniere A, Kroemer G (2006) Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6(10):715–727. doi:10.1038/nri1936

    Article  CAS  PubMed  Google Scholar 

  2. Muller AJ, Scherle PA (2006) Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6(8):613–625. doi:10.1038/nrc1929

    Article  CAS  PubMed  Google Scholar 

  3. Allavena P, Sica A, Solinas G, Porta C, Mantovani A (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66(1):1–9. doi:10.1016/j.critrevonc.2007.07.004

    Article  PubMed  Google Scholar 

  4. Locati M, Mantovani A, Sica A (2013) Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 120:163–184. doi:10.1016/B978-0-12-417028-5.00006-5

    Article  CAS  PubMed  Google Scholar 

  5. Fujimoto J, Sakaguchi H, Aoki I, Tamaya T (2000) Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers. Cancer Res 60(10):2632–2635

    CAS  PubMed  Google Scholar 

  6. Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res 5(5):1107–1113

    CAS  PubMed  Google Scholar 

  7. Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17(3):445–451

    CAS  PubMed  Google Scholar 

  8. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629

    CAS  PubMed  Google Scholar 

  9. Lee AH, Happerfield LC, Bobrow LG, Millis RR (1997) Angiogenesis and inflammation in invasive carcinoma of the breast. J Clin Pathol 50(8):669–673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hanada T, Nakagawa M, Emoto A, Nomura T, Nasu N, Nomura Y (2000) Prognostic value of tumor-associated macrophage count in human bladder cancer. Int J Urol 7(7):263–269

    Article  CAS  PubMed  Google Scholar 

  11. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555

    Article  CAS  PubMed  Google Scholar 

  12. Wang HW, Joyce JA (2010) Alternative activation of tumor-associated macrophages by IL-4: priming for protumoral functions. Cell Cycle 9(24):4824–4835. doi:10.4161/cc.9.24.14322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pedroza-Gonzalez A, Xu K, Wu TC, Aspord C, Tindle S, Marches F, Gallegos M, Burton EC, Savino D, Hori T, Tanaka Y, Zurawski S, Zurawski G, Bover L, Liu YJ, Banchereau J, Palucka AK (2011) Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med 208(3):479–490. doi:10.1084/jem.20102131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nevala WK, Vachon CM, Leontovich AA, Scott CG, Thompson MA, Markovic SN, Melanoma Study Group of the Mayo Clinic Cancer C (2009) Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res 15(6):1931–1939. doi:10.1158/1078-0432.CCR-08-1980

    Article  Google Scholar 

  15. Gao J, Wu Y, Su Z, Amoah Barnie P, Jiao Z, Bie Q, Lu L, Wang S, Xu H (2014) Infiltration of alternatively activated macrophages in cancer tissue is associated with MDSC and Th2 polarization in patients with esophageal cancer. PLoS One 9(8):e104453. doi:10.1371/journal.pone.0104453

    Article  PubMed  PubMed Central  Google Scholar 

  16. Baier PK, Wolff-Vorbeck G, Eggstein S, Baumgartner U, Hopt UT (2005) Cytokine expression in colon carcinoma. Anticancer Res 25(3B):2135–2139

    CAS  PubMed  Google Scholar 

  17. Li J, Wang Z, Mao K, Guo X (2014) Clinical significance of serum T helper 1/T helper 2 cytokine shift in patients with non-small cell lung cancer. Oncol Lett 8(4):1682–1686. doi:10.3892/ol.2014.2391

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Shirota H, Klinman DM, Ito SE, Ito H, Kubo M, Ishioka C (2017) IL4 from T follicular helper cells downregulates antitumor immunity. Cancer Immunol Res 5(1):61–71. doi:10.1158/2326-6066.CIR-16-0113

    Article  CAS  PubMed  Google Scholar 

  19. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1(4):389–402. doi:10.1016/j.stem.2007.08.001

    Article  CAS  PubMed  Google Scholar 

  20. Li Z, Jiang J, Wang Z, Zhang J, Xiao M, Wang C, Lu Y, Qin Z (2008) Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis. Cancer Res 68(21):8687–8694. doi:10.1158/0008-5472.CAN-08-0449

    Article  CAS  PubMed  Google Scholar 

  21. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16(2):91–102. doi:10.1016/j.ccr.2009.06.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1(6):515–520. doi:10.1038/82771

    Article  CAS  PubMed  Google Scholar 

  23. Shirota H, Klinman DM (2011) CpG-conjugated apoptotic tumor cells elicit potent tumor-specific immunity. Cancer Immunol Immunother 60(5):659–669. doi:10.1007/s00262-011-0973-y

    Article  CAS  PubMed  Google Scholar 

  24. Pulaski BA, Terman DS, Khan S, Muller E, Ostrand-Rosenberg S (2000) Cooperativity of Staphylococcal aureus enterotoxin B superantigen, major histocompatibility complex class II, and CD80 for immunotherapy of advanced spontaneous metastases in a clinically relevant postoperative mouse breast cancer model. Cancer Res 60:2710–2715

    CAS  PubMed  Google Scholar 

  25. Shirota Y, Shirota H, Klinman DM (2012) Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells. J Immunol 188(4):1592–1599. doi:10.4049/jimmunol.1101304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aspeslagh S, Postel-Vinay S, Rusakiewicz S, Soria JC, Zitvogel L, Marabelle A (2016) Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer 52:50–66. doi:10.1016/j.ejca.2015.08.021

    Article  CAS  PubMed  Google Scholar 

  27. Sugamura K, Ishii N, Weinberg AD (2004) Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 4(6):420–431. doi:10.1038/nri1371

    Article  CAS  PubMed  Google Scholar 

  28. Shirota H, Tross D, Klinman DM (2015) CpG oligonucleotides as cancer vaccine adjuvants. Vaccines (Basel) 3(2):390–407. doi:10.3390/vaccines3020390

    Article  Google Scholar 

  29. Shirota H, Klinman DM (2014) Recent progress concerning CpG DNA and its use as a vaccine adjuvant. Expert Rev Vaccines 13(2):299–312. doi:10.1586/14760584.2014.863715

    Article  CAS  PubMed  Google Scholar 

  30. Villacres MC, Bergmann CC (1999) Enhanced cytotoxic T cell activity in IL-4-deficient mice. J Immunol 162(5):2663–2670

    CAS  PubMed  Google Scholar 

  31. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182(8):4499–4506. doi:10.4049/jimmunol.0802740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prokopchuk O, Liu Y, Henne-Bruns D, Kornmann M (2005) Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. Br J Cancer 92(5):921–928. doi:10.1038/sj.bjc.6602416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Venmar KT, Carter KJ, Hwang DG, Dozier EA, Fingleton B (2014) IL4 receptor ILR4α regulates metastatic colonization by mammary tumors through multiple signaling pathways. Cancer Res 74(16):4329–4340. doi:10.0008-5472.CAN-14-0093

  34. Yang CY, Liu HW, Tsai YC, Tseng JY, Liang SC, Chen CY, Lian WN, Wei MC, Lu M, Lu RH, Lin CH, Jiang JK (2015) Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer. Cancer Biol Ther 16(11):1641–1650. doi:10.1080/15384047.2015.1095397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449. doi:10.1158/0008-5472.CAN-07-6621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 5:75. doi:10.3389/fphys.2014.00075 eCollection 2014

    Article  PubMed  PubMed Central  Google Scholar 

  37. Valkovic T, Dobrila F, Melato M, Sasso F, Rizzardi C, Jonjic N (2002) Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma. Virchows Arch 440(6):583–588. doi:10.1007/s004280100458

    Article  CAS  PubMed  Google Scholar 

  38. Shieh YS, Hung YJ, Hsieh CB, Chen JS, Chou KC, Liu SY (2009) Tumor-associated macrophage correlated with angiogenesis and progression of mucoepidermoid carcinoma of salivary glands. Ann Surg Oncol 16(3):751–760. doi:10.1245/s10434-008-0259-6

    Article  PubMed  Google Scholar 

  39. Ries CH, Hoves S, Cannarile MA, Ruttinger D (2015) CSF-1/CSF-1R targeting agents in clinical development for cancer therapy. Curr Opin Pharmacol 23:45–51. doi:10.1016/j.coph.2015.05.008

    Article  CAS  PubMed  Google Scholar 

  40. Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C (2002) Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 196(4):541–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cai X, Yin Y, Li N, Zhu D, Zhang J, Zhang CY, Zen K (2012) Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J Mol Cell Biol 4(5):341–343. doi:10.1093/jmcb/mjs044

    Article  CAS  PubMed  Google Scholar 

  42. Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM (2015) TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol Res 3(5):518–525. doi:10.1158/2326-6066.CIR-14-0232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Takeuchi T, Ueki T, Sasaki Y, Kajiwara T, Li B, Moriyama N, Kawabe K (1997) Th2-like response and antitumor effect of anti-interleukin-4 mAb in mice bearing renal cell carcinoma. Cancer Immunol Immunother 43(6):375–381

    Article  CAS  PubMed  Google Scholar 

  44. Tourangeau LM, Kavanaugh A, Wasserman SI (2011) The role of monoclonal antibodies in the treatment of severe asthma. Ther Adv Respir Dis 5(3):183–194. doi:10.1177/1753465811400489

    Article  CAS  PubMed  Google Scholar 

  45. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461. doi:10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Hidekazu Shirota.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interests.


This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI Grant No. 25430103 and 16K07106, Japan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ito, Se., Shirota, H., Kasahara, Y. et al. IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model. Cancer Immunol Immunother 66, 1485–1496 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: