Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals Journal Article
| Authors: | Mitsui, J.; Nishikawa, H.; Muraoka, D.; Wang, L.; Noguchi, T.; Sato, E.; Kondo, S.; Allison, J. P.; Sakaguchi, S.; Old, L. J.; Kato, T.; Shiku, H. |
| Article Title: | Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals |
| Abstract: | Purpose: Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25 + Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge. Experimental Design: The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti-glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line). Results: Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling. Conclusions: This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. ©2010 AACR. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; unclassified drug; drug potentiation; nonhuman; flow cytometry; cd8 antigen; transcription factor foxp3; antigen expression; cd8+ t lymphocyte; t lymphocyte; cd8-positive t-lymphocytes; lymphocytes, tumor-infiltrating; animal cell; mouse; animals; mice; cell infiltration; antineoplastic combined chemotherapy protocols; animal experiment; animal model; antineoplastic activity; cancer model; mice, inbred balb c; monoclonal antibody; cytokine; cd4+ cd25+ t lymphocyte; regulatory t lymphocyte; lymphocyte activation; antibodies, monoclonal; immune response; t-lymphocytes, regulatory; quantitative analysis; neoplasms, experimental; tumor immunity; immunomodulation; upregulation; immunostimulation; antigens, cd; enzyme-linked immunosorbent assay; immunologic factors; cytotoxic t lymphocyte antigen 4; cytokine release; glucocorticoid induced tumor necrosis factor receptor; tumor rejection; cell separation; interleukin 2 receptor alpha; qualitative analysis; receptors, tumor necrosis factor; receptors, nerve growth factor; monoclonal antibody ctla 4; monoclonal antibody gitr |
| Journal Title: | Clinical Cancer Research |
| Volume: | 16 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-05-15 |
| Start Page: | 2781 |
| End Page: | 2791 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-09-3243 |
| PUBMED: | 20460483 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: CCREF" - "Source: Scopus" |
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