This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, K. Articles by Abrams, S. I. Search for Related Content PubMed PubMed Citation Articles by Liu, K. Articles by Abrams, S. I.

Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequences of Fas-Mediated Cytotoxicity and Altered IFN--Regulated Gene Expression

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Scott I. Abrams, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room 5B46, 10 Center Drive, Bethesda, MD 20892-1402. Phone: 301-402-6267; Fax: 301-496-2756; E-mail: sa47z{at}nih.gov.

Antitumor responses can be induced in patients via active or adoptive immunotherapy, yet complete tumor eradication occurs infrequently. This paradox in tumor immunology led us to address two questions: (a) Does an antitumor response, which is intended to destroy the aberrant target population, also at the same time select for aggressive tumor variants (ATV) in vivo? (b) If this process does occur, what is the contribution of the perforin- or Fas-mediated effector mechanism in the immune selection of such ATV? Here, in an experimental mouse lung metastasis model, we showed that ATV generated either naturally in vivo or in vitro by anti-Fas selection resembled each other biologically and genetically as judged by enhanced tumor growth and genome-scale gene expression profiling, respectively. Furthermore, ATV that survived CTL adoptive immunotherapy displayed an even more profound loss of Fas expression and function as well as enhanced malignant proficiency in vivo. ATV, however, retained sensitivity to perforin-mediated lysis in vitro. Lastly, such ATV displayed a diminished responsiveness in their expression of IFN--regulated genes, including those mechanistically linked to Fas-mediated death (i.e., Fas and caspase-1). Overall, we showed that (a) immune selection did occur in vivo and played an important role in the emergence of ATV, (b) ATV bearing a Fas-resistant phenotype was a chief consequence of immune selection, and (c) an overall diminished responsiveness of IFN--regulated gene expression was characteristic of ATV. Thus, in this model, Fas-mediated cytotoxicity, in concert with IFN--regulated gene expression, mechanistically constituted significant determinants of immune selection of ATV in vivo.

This article has been cited by other articles:

				R. Lengagne, S. Graff-Dubois, M. Garcette, L. Renia, M. Kato, J.-G. Guillet, V. H. Engelhard, M.-F. Avril, J.-P. Abastado, and A. Prevost-Blondel Distinct Role for CD8 T Cells toward Cutaneous Tumors and Visceral Metastases J. Immunol., January 1, 2008; 180(1): 130 - 137. [Abstract] [Full Text] [PDF]

				D. Yang, N. ud Din, D. D. Browning, S. I. Abrams, and K. Liu Targeting Lymphotoxin {beta} Receptor with Tumor-Specific T Lymphocytes for Tumor Regression Clin. Cancer Res., September 1, 2007; 13(17): 5202 - 5210. [Abstract] [Full Text] [PDF]

				T. F. Gajewski On the TRAIL Toward Death Receptor-Based Cancer Therapeutics J. Clin. Oncol., April 10, 2007; 25(11): 1305 - 1307. [Full Text] [PDF]

				D. Yang, M. Thangaraju, K. Greeneltch, D. D. Browning, P. V. Schoenlein, T. Tamura, K. Ozato, V. Ganapathy, S. I. Abrams, and K. Liu Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells Cancer Res., April 1, 2007; 67(7): 3301 - 3309. [Abstract] [Full Text] [PDF]

				S. Abouzahr, G. Bismuth, C. Gaudin, O. Caroll, P. Van Endert, A. Jalil, J. Dausset, I. Vergnon, C. Richon, A. Kauffmann, et al. Identification of target actin content and polymerization status as a mechanism of tumor resistance after cytolytic T lymphocyte pressure PNAS, January 31, 2006; 103(5): 1428 - 1433. [Abstract] [Full Text] [PDF]