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 Suzuki, E. Articles by Albelda, S. M. Search for Related Content PubMed PubMed Citation Articles by Suzuki, E. Articles by Albelda, S. M.

Gemcitabine Selectively Eliminates Splenic Gr-1⁺/CD11b⁺ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity

Authors' Affiliation: Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Steven M. Albelda, Thoracic Oncology Research Laboratory, University of Pennsylvania, Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-573-9969; Fax: 215-573-4469; E-mail: albelda{at}mail.med.upenn.edu.

Purpose: Myeloid suppressor (Gr-1⁺/CD11b⁺) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8⁺ T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist.

Experimental Design: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1⁺/CD11b⁺) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-ß.

Results: This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4⁺ T cells, CD8⁺ T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8⁺ T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-ß markedly enhanced antitumor efficacy.

Conclusions: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.

This article has been cited by other articles:

				T. J. Stewart, D. J. Liewehr, S. M. Steinberg, K. M. Greeneltch, and S. I. Abrams Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b+Gr-1+ Myeloid Cells J. Immunol., July 1, 2009; 183(1): 117 - 128. [Abstract] [Full Text] [PDF]

				G. V. Shurin, I. L. Tourkova, R. Kaneno, and M. R. Shurin Chemotherapeutic Agents in Noncytotoxic Concentrations Increase Antigen Presentation by Dendritic Cells via an IL-12-Dependent Mechanism J. Immunol., July 1, 2009; 183(1): 137 - 144. [Abstract] [Full Text] [PDF]

				S. K. Bunt, V. K. Clements, E. M. Hanson, P. Sinha, and S. Ostrand-Rosenberg Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4 J. Leukoc. Biol., June 1, 2009; 85(6): 996 - 1004. [Abstract] [Full Text] [PDF]

				S. Ostrand-Rosenberg and P. Sinha Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer J. Immunol., April 15, 2009; 182(8): 4499 - 4506. [Abstract] [Full Text] [PDF]

				N. Nausch, I. E. Galani, E. Schlecker, and A. Cerwenka Mononuclear myeloid-derived "suppressor" cells express RAE-1 and activate natural killer cells Blood, November 15, 2008; 112(10): 4080 - 4089. [Abstract] [Full Text] [PDF]

				P. Sinha, C. Okoro, D. Foell, H. H. Freeze, S. Ostrand-Rosenberg, and G. Srikrishna Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells J. Immunol., October 1, 2008; 181(7): 4666 - 4675. [Abstract] [Full Text] [PDF]

				S. Watanabe, K. Deguchi, R. Zheng, H. Tamai, L.-x. Wang, P. A. Cohen, and S. Shu Tumor-Induced CD11b+Gr-1+ Myeloid Cells Suppress T Cell Sensitization in Tumor-Draining Lymph Nodes J. Immunol., September 1, 2008; 181(5): 3291 - 3300. [Abstract] [Full Text] [PDF]

				S. K. Bunt, L. Yang, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Reduced Inflammation in the Tumor Microenvironment Delays the Accumulation of Myeloid-Derived Suppressor Cells and Limits Tumor Progression Cancer Res., October 15, 2007; 67(20): 10019 - 10026. [Abstract] [Full Text] [PDF]

				R. Marhaba, M. Vitacolonna, D. Hildebrand, M. Baniyash, P. Freyschmidt-Paul, and M. Zoller The Importance of Myeloid-Derived Suppressor Cells in the Regulation of Autoimmune Effector Cells by a Chronic Contact Eczema J. Immunol., October 15, 2007; 179(8): 5071 - 5081. [Abstract] [Full Text] [PDF]

				C. E. Clark, S. R. Hingorani, R. Mick, C. Combs, D. A. Tuveson, and R. H. Vonderheide Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion Cancer Res., October 1, 2007; 67(19): 9518 - 9527. [Abstract] [Full Text] [PDF]

				E. Celis Toll-like Receptor Ligands Energize Peptide Vaccines through Multiple Paths Cancer Res., September 1, 2007; 67(17): 7945 - 7947. [Abstract] [Full Text] [PDF]

				I. Fricke, N. Mirza, J. Dupont, C. Lockhart, A. Jackson, J.-H. Lee, J. A. Sosman, and D. I. Gabrilovich Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses Clin. Cancer Res., August 15, 2007; 13(16): 4840 - 4848. [Abstract] [Full Text] [PDF]

				H.-J. Ko, Y.-J. Kim, Y.-S. Kim, W.-S. Chang, S.-Y. Ko, S.-Y. Chang, S. Sakaguchi, and C.-Y. Kang A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model Cancer Res., August 1, 2007; 67(15): 7477 - 7486. [Abstract] [Full Text] [PDF]

				P. Sinha, V. K. Clements, S. K. Bunt, S. M. Albelda, and S. Ostrand-Rosenberg Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response J. Immunol., July 15, 2007; 179(2): 977 - 983. [Abstract] [Full Text] [PDF]

				C. Liu, S. Yu, J. Kappes, J. Wang, W. E. Grizzle, K. R. Zinn, and H.-G. Zhang Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host Blood, May 15, 2007; 109(10): 4336 - 4342. [Abstract] [Full Text] [PDF]

				P. Sinha, V. K. Clements, A. M. Fulton, and S. Ostrand-Rosenberg Prostaglandin E2 Promotes Tumor Progression by Inducing Myeloid-Derived Suppressor Cells Cancer Res., May 1, 2007; 67(9): 4507 - 4513. [Abstract] [Full Text] [PDF]

				J. Vieweg, Z. Su, P. Dahm, and S. Kusmartsev Reversal of Tumor-Mediated Immunosuppression Clin. Cancer Res., January 15, 2007; 13(2): 727s - 732s. [Abstract] [Full Text] [PDF]

				K. C. McKenna and J. A. Kapp Accumulation of Immunosuppressive CD11b+ Myeloid Cells Correlates with the Failure to Prevent Tumor Growth in the Anterior Chamber of the Eye J. Immunol., August 1, 2006; 177(3): 1599 - 1608. [Abstract] [Full Text] [PDF]