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Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors

Cancer Immunology, Immunotherapy volume 57, pages 701–718 (2008)Cite this article

Abstract

Although animals can be immunized against the growth of some tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they have become established have been disappointing even when strongly immunogenic tumors were used as target. In this paper, we demonstrate that the failure to achieve an efficient immunological treatment against an established strongly immunogenic murine fibrosarcoma was paralleled with the emergence of a state of immunological unresponsiveness (immunological eclipse) against tumor antigens observed when the tumor surpassed the critical size of 500 mm3. In turn, the onset of the immunological eclipse was coincidental with the onset of a systemic inflammatory condition characterized by a high number of circulating and splenic polymorphonucleated neutrophils (PMN) displaying activation and Gr1+Mac1+ phenotype and an increasing serum concentration of the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 cytokines and C-reactive protein (CRP) and serum A amyloid (SAA) phase acute proteins. Treatment of tumor-bearing mice with a single low dose (0.75 mg/kg) of the synthetic corticoid dexamethasone (DX) significantly reduced all the systemic inflammatory parameters and simultaneously reversed the immunological eclipse, as evidenced by the restoration of specific T-cell-dependent concomitant immunity, ability of spleen cells to transfer anti-tumor activity and recovery of T-cell signal transduction molecules. Two other anti-inflammatory treatments by using indomethacin or dimeric TNF-α receptor, also partially reversed the immunological eclipse although the effect was not as striking as that observed with DX. The reversion of the immunological eclipse was not enough on its own to inhibit the primary growing tumor. However, when we used the two-step strategy of inoculating DX to reverse the eclipse and then dendritic cells loaded with tumor antigens (DC) as an immunization booster, a significant inhibition of the growth of both established tumors and remnant tumor cells after excision of large established tumors was observed, despite the fact that the vaccination alone (DC) had no effect or even enhanced tumor growth in certain circumstances. The two-step strategy of tumor immunotherapy that we present is based on the rationale that it is necessary to eliminate or ameliorate the immunological eclipse as a precondition to allow an otherwise ineffective anti-tumor immunological therapy to have a chance to be successful.

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Acknowledgments

This work was supported by grants from CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Fundación Roemmers and Agencia Nacional de Promoción Científica y Tecnológica (PICT 05-38197/2005), Argentina. One of the authors (M. Vulcano) was a recipient of an International Cancer Technology Transfer Fellowship (ICRETT 2005) from the International Union Against Cancer (UICC). The authors are grateful to Dr. Richmond T. Prehn and Dra. Christiane D. Pasqualini for critical discussion of this article.

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  1. Marisa Vulcano

    Present address: Research Laboratory in Immunology and Inflammation, Istituto Clinico Humanitas, Rozzano, Milan, Italy

Affiliations

  1. División Medicina Experimental (ILEX CONICET), Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Paula Chiarella, Juan Bruzzo, Andrea Maglioco, Gabriela Camerano, Martín A. Isturiz, Graciela I. Dran, Oscar D. Bustuoabad & Raúl A. Ruggiero

  2. División Inmunología, Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Marisa Vulcano, Gabriela Fernández, Romina Fernández Brando & Martín A. Isturiz

  3. División Inmunología Oncológica, Instituto de Investigaciones Hematológicas (IIHEMA), Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Mónica Vermeulen

  4. Instituto de Estudios Oncológicos (IEO), Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Silvia Vanzulli

  5. Centro de Estudio y Tratamiento Oncológico (CETRO), Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425, Buenos Aires, Argentina

    Víctor Palacios

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  1. Paula Chiarella
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Correspondence to Raúl A. Ruggiero.

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Chiarella, P., Vulcano, M., Bruzzo, J. et al. Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors. Cancer Immunol Immunother 57, 701–718 (2008). https://doi.org/10.1007/s00262-007-0410-4

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Keywords

  • Tumor
  • Immunotherapy
  • Dendritic cells
  • Systemic inflammation