Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts Journal Article
| Authors: | Quezada, S. A.; Simpson, T. R.; Peggs, K. S.; Merghoub, T.; Vider, J.; Fan, X.; Blasberg, R.; Yagita, H.; Muranski, P.; Antony, P. A.; Restifo, N. P.; Allison, J. P. |
| Article Title: | Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts |
| Abstract: | Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation. © 2010 Quezada et al. |
| Keywords: | controlled study; cancer risk; nonhuman; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; cell division; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; melanoma; animal experiment; animal model; cell differentiation; antineoplastic activity; cytotoxicity; immunofluorescence; in vitro study; immunoreactivity; mice, transgenic; lymphocytopenia; cancer inhibition; lymphocyte differentiation; gamma interferon; antigen recognition; cd4+ t lymphocyte; cd4-positive t-lymphocytes; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; melanoma, experimental; adoptive transfer; interferon-gamma; disease models, animal; cytokine release; tyrosinase related protein 1; cell expansion; lymphocyte antigen receptor; cell transfer; trypsin; leukemia, t-cell; gamma interferon antibody; ia antibody; tumor necrosis factor alpha antibody |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 207 |
| Issue: | 3 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2010-03-15 |
| Start Page: | 637 |
| End Page: | 650 |
| Language: | English |
| DOI: | 10.1084/jem.20091918 |
| PUBMED: | 20156971 |
| PROVIDER: | scopus |
| PMCID: | PMC2839156 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 31" - "Export Date: 20 April 2011" - "CODEN: JEMEA" - "Source: Scopus" |
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