Induction of T cell responses and recruitment of an inflammatory dendritic cell subset following tumor immunotherapy with Mycobacterium smegmatis
- 661 Downloads
Mycobacteria and their cell wall components have been used with varying degrees of success to treat tumors, and Mycobacterium bovis BCG remains in use as a standard treatment for superficial bladder cancer. Mycobacterial immunotherapy is very effective in eliciting local immune responses against solid tumors when administered topically; however, its effectiveness in eliciting adaptive immune responses has been variable. Using a subcutaneous mouse thymoma model, we investigated whether immunotherapy with Mycobacterium smegmatis, a fast-growing mycobacterium of low pathogenicity, induces a systemic adaptive immune response. We found that M. smegmatis delivered adjacent to the tumor site elicited a systemic anti-tumor immune response that was primarily mediated by CD8+ T cells. Of note, we identified a CD11c+CD40intCD11bhiGr-1+ inflammatory DC population in the tumor-draining lymph nodes that was found only in mice treated with M. smegmatis. Our data suggest that, rather than rescuing the function of the DC already present in the tumor and/or tumor-draining lymph node, M. smegmatis treatment may promote anti-tumor immune responses by inducing the involvement of a new population of inflammatory cells with intact function.
KeywordsMycobacterium smegmatis Immunotherapy Dendritic cell Thymoma Mycobacteria BCG
This work was supported by research grants from the Cancer Society of New Zealand and from the Malaghan Institute of Medical Research. Joanna Kirman is the Wellington Medical Research Foundation Malaghan Haematology Fellow; Sabine Kuhn was supported by a PhD scholarship from DAAD and Victoria University of Wellington. The authors thank the Biomedical Research Unit at the Malaghan Institute for their excellent animal husbandry, and Kelly Prendergast and Lindsay Ancelet for assistance with experiments.
Conflict of interest
The authors declare that they have no conflicts of interest.
- 1.Coley WB (1910) The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med 3 (Surg Sect):1–48Google Scholar
- 11.Ayari C, LaRue H, Hovington H, Decobert M, Harel F, Bergeron A, Tetu B, Lacombe L, Fradet Y (2009) Bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus Calmette-Guerin immunotherapy. Eur Urol 55(6):1386–1395. doi: 10.1016/j.eururo.2009.01.040 PubMedCrossRefGoogle Scholar
- 12.Higuchi T, Shimizu M, Owaki A, Takahashi M, Shinya E, Nishimura T, Takahashi H (2009) A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth. Cancer Immunol Immunother 58(8):1245–1255. doi: 10.1007/s00262-008-0643-x PubMedCrossRefGoogle Scholar
- 18.Patel PM, Sim S, O’Donnell DO, Protheroe A, Beirne D, Stanley A, Tourani JM, Khayat D, Hancock B, Vasey P, Dalgleish A, Johnston C, Banks RE, Selby PJ (2008) An evaluation of a preparation of Mycobacterium vaccae (SRL172) as an immunotherapeutic agent in renal cancer. Eur J Cancer 44(2):216–223. doi: 10.1016/j.ejca.2007.11.003 PubMedCrossRefGoogle Scholar
- 24.Sylvester RJ, van der Meijden AP, Oosterlinck W, Hoeltl W, Bono AV (2003) The side effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do not predict its efficacy: results from a European organisation for research and treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol 44(4):423–428PubMedCrossRefGoogle Scholar
- 25.Pierre-Audigier C, Jouanguy E, Lamhamedi S, Altare F, Rauzier J, Vincent V, Canioni D, Emile JF, Fischer A, Blanche S, Gaillard JL, Casanova JL (1997) Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency. Clin Infect Dis 24(5):982–984PubMedCrossRefGoogle Scholar
- 27.Cheadle EJ, O’Donnell D, Selby PJ, Jackson AM (2005) Closely related mycobacterial strains demonstrate contrasting levels of efficacy as antitumor vaccines and are processed for major histocompatibility complex class I presentation by multiple routes in dendritic cells. Infect Immun 73(2):784–794. doi: 10.1128/IAI.73.2.784-794.2005 PubMedCrossRefGoogle Scholar
- 30.Le Borgne M, Etchart N, Goubier A, Lira SA, Sirard JC, van Rooijen N, Caux C, Ait-Yahia S, Vicari A, Kaiserlian D, Dubois B (2006) Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24(2):191–201. doi: 10.1016/j.immuni.2006.01.005 PubMedCrossRefGoogle Scholar
- 32.Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A, von Andrian UH (2001) Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med 194(9):1361–1373PubMedCrossRefGoogle Scholar