Abstract #LB-158: Th1 cell therapy to overcome immunosuppressive tumor-escape: From mouse model to a novel clinical application
Authors: Takashi Nishimura, Kenji Chamoto, Daiko Wakita, Takayuki Ohkuri, Hidemitsu Kitamura, Yuji Togashi
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

It is difficult to induce tumor-specific CTL in tumor-bearing host because of immunosuppressive tumor escape mechanisms. Therefore, it is of great important to evaluate (i) how T cell-mediated immune responses are suppressed at draining lymph node and/or tumor site and (ii) how we can overcome the strong immunosuppressive tumor escape mechanisms to induce tumor-specific CTL essential for tumor rejection. As immunosuppressive effector cells at tumor local site, we examined the following three types of cells; i) CD4+ CD25+ FOXP3+ Treg, ii) myeoid-derived suppressor cells (MDSC) and iii) IL-17-producing tumor-infiltrating \#947;\#948;T cells (T\#947;\#948;17). Carcinoma cells, especially CD133+ cancer stem cells induced the accumulation of Treg cells at draining lymph node via TGF-\#946; production. The inhibition of Treg accumulation by anti-CD25 mAb plus anti-TGF-\#946; resulted in the inhibition of carcinoma growth, indicating that Treg cells were actually involved in immunosuppression in tumor-bearing host. During growth of tumor, abnormal increase of the number of CD11b+Gr-1+ immature myeloid cells (ImC) were observed. Although Gr-1mid or Gr-1high ImC, which increased in spleen of tumor-bearing mice dependently on IL-6 exhibited no significant immunosuppression, Gr-1high neutrophil-like MDSC and Gr-1low M\#981;-like MDSC showed strong immunosuppression. Depletion of MDSC by anti-IL-6R mAb or gemcitabine caused the recovery of T cell responses and induced the inhibition of tumor growth. Finally, we examined the role of T\#947;\#948;17 cells, which are major IL-17-producing cells in tumor sites. Here, we first demonstrated that T\#947;\#948;17 cells, generated in response to tumor microenvironment factors including IL-23, IL-6, and TGF-\#946;, promote angiogenesis and the subsequent tumor progression. Thus, Treg, ImC and IL-17 would be promising targets for establishment of a novel strategy in cancer therapy. To overcome such strong immunosuppression in tumor-bearing state, we have been proposed that activation of type-1 immunity by TLR-9-ligand, CpG or Th1 cells is very important. Especially, Th1 cell therapy accelerated the generation of tumor-specific CTL and inhibited the accumulation of Treg. Thus, it appeared that the introduction of Th1-dependent immunity at tumor local site is crucial to overcome immunosuppressive tumor escape mechanisms and induce a successful immunotherapy of tumor. We have already established the protocol to propagate human tumor-specific Th1 cells by novel tumor helper peptides. Using the original protocol, we succeeded in not only identifying the novel survivin and MAGE-A4 helper peptides, but also inducing Survivin- and MAGE-A4-specific Th1 cells in human system. We are now planning a clinical trial of Th1 cell therapy combined helper peptide against human cancer after evaluating its rationality in hu-mouse therapy model.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-158.