Display options
Cite
Muthuswamy R, Wang L, Pitteroff J, et al. Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction. J Immunother Cancer. 2015;3:6doi: 10.1186/s40425-015-0050-8.
Muthuswamy, R., Wang, L., Pitteroff, J., Gingrich, J. R., & Kalinski, P. (2015). Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction. Journal for immunotherapy of cancer, 36. https://doi.org/10.1186/s40425-015-0050-8
Muthuswamy, Ravikumar, et al. "Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction." Journal for immunotherapy of cancer vol. 3 (2015): 6. doi: https://doi.org/10.1186/s40425-015-0050-8
Muthuswamy R, Wang L, Pitteroff J, Gingrich JR, Kalinski P. Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction. J Immunother Cancer. 2015 Mar 24;3:6. doi: 10.1186/s40425-015-0050-8. eCollection 2015. PMID: 25806105; PMCID: PMC4371844.
Copy Download .nbib Format: NLM
Share it on

J Immunother Cancer. 2015 Mar 24;3:6. doi: 10.1186/s40425-015-0050-8. eCollection 2015.

Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction.

Journal for immunotherapy of cancer

Ravikumar Muthuswamy, Liwen Wang, Jamie Pitteroff, Jeffrey R Gingrich, Pawel Kalinski

Affiliations

  1. Departments of Sugery, University of Pittsburgh, Pittsburgh, PA 15213 USA.
  2. Department of Urology, University of Pittsburgh, Pittsburgh, PA 15213 USA.
  3. Departments of Sugery, University of Pittsburgh, Pittsburgh, PA 15213 USA ; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15213 USA ; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213 USA ; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 USA ; Department of Surgery, University of Pittsburgh, Hillman Cancer Center, UPCI Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh, PA 15213 USA.

PMID: 25806105 PMCID: PMC4371844 DOI: 10.1186/s40425-015-0050-8

Abstract

BACKGROUND: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs.

METHODS: Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data.

RESULTS: Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and Treg-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage.

CONCLUSIONS: The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases.

Keywords: BCG; Bladder cancer; Chemokines; Effector T cells; IFNα; Immunomodulation; Poly-I :C; Regulatory T cells; TLR3; Tumor microenvironment

References

  1. N Engl J Med. 2005 Dec 22;353(25):2654-66 - PubMed
  2. Cancer Res. 2011 Dec 15;71(24):7463-70 - PubMed
  3. J Pathol. 2009 Jan;217(1):21-31 - PubMed
  4. Cancer Res. 2007 Jan 1;67(1):354-61 - PubMed
  5. Int J Cancer. 2014 May 15;134(10):2393-402 - PubMed
  6. Cell Immunol. 2009;256(1-2):12-8 - PubMed
  7. Int J Cancer. 2010 Nov 15;127(10):2300-12 - PubMed
  8. J Leukoc Biol. 2003 Aug;74(2):277-86 - PubMed
  9. J Clin Oncol. 2011 May 20;29(15):1949-55 - PubMed
  10. Nat Med. 2004 Sep;10(9):942-9 - PubMed
  11. J Immunol. 2010 Jan 15;184(2):591-7 - PubMed
  12. Int J Oncol. 2005 Jan;26(1):41-7 - PubMed
  13. J Urol. 2010 Nov;184(5):1915-9 - PubMed
  14. Cancer Res. 2004 Nov 15;64(22):8451-5 - PubMed
  15. PLoS One. 2012;7(6):e38711 - PubMed
  16. Cell Immunol. 2007 Feb;245(2):111-8 - PubMed
  17. Cancer Res. 2012 Aug 1;72(15):3735-43 - PubMed
  18. BMC Cancer. 2013 Jul 05;13:332 - PubMed
  19. Immunol Invest. 2012;41(6-7):635-57 - PubMed
  20. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3967-72 - PubMed
  21. Science. 2006 Sep 29;313(5795):1960-4 - PubMed
  22. Clin Cancer Res. 2015 Jan 15;21(2):303-11 - PubMed
  23. J Urol. 2009 Apr;181(4):1571-80 - PubMed
  24. Clin Cancer Res. 2010 Dec 15;16(24):6122-31 - PubMed
  25. J Urol. 2008 Jan;179(1):53-6 - PubMed
  26. Cancer Res. 2009 Apr 1;69(7):3077-85 - PubMed
  27. Cancer Immunol Immunother. 2010 Oct;59(10):1543-9 - PubMed
  28. Nat Immunol. 2009 Nov;10(11):1200-7 - PubMed
  29. Oncoimmunology. 2012 Sep 1;1(6):829-839 - PubMed
  30. Cancer Cell. 2013 Nov 11;24(5):631-44 - PubMed
  31. BMC Urol. 2012 Jun 13;12:18 - PubMed
  32. J Urol. 2002 Feb;167(2 Pt 2):891-3; discussion 893-5 - PubMed
  33. J Immunol. 2012 Feb 1;188(3):1019-26 - PubMed
  34. J Clin Oncol. 2009 Dec 10;27(35):5944-51 - PubMed
  35. J Immunol. 2013 Jun 15;190(12):6673-80 - PubMed
  36. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18538-43 - PubMed
  37. J Urol. 2005 Mar;173(3):990-5 - PubMed
  38. Nat Rev Cancer. 2012 Mar 15;12 (4):298-306 - PubMed
  39. Urol Oncol. 2014 Jan;32(1):35.e21-30 - PubMed
  40. Gastroenterology. 2010 Apr;138(4):1429-40 - PubMed
  41. Cancer Res. 2008 Jul 15;68(14):5972-8 - PubMed
  42. Urol Oncol. 2009 May-Jun;27(3):258-62 - PubMed
  43. Hum Pathol. 2004 Jul;35(7):808-16 - PubMed
  44. J Immunol. 2000 May 1;164(9):4507-12 - PubMed

Publication Types

Grant support