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

PAULA CHIARELLA; MARISA VULCANO; JUAN BRUZZO; MÓNICA VERMEULEN; SILVIA VANZULLI; ANDREA MAGLIOCO; GABRIELA CAMERANO; VÍCTOR PALACIOS; GABRIELA FERNÁNDEZ; ROMINA FERNÁNDEZ BRANDO; MARTÍN A. ISTURIZ; GRACIELA I. DRAN; OSCAR D. BUSTUOABAD; RAÚL A. RUGGIERO

CANCER IMMUNOLOGY IMMUNOTHERAPY

Año: 2007 p. 701 - 718

0340-7004

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-_, IL-1_ and IL-6 cytokines and C-reactive protein (CRP) and serum A amyloid (SAA) phase acute proteins. Treatment of tumorbearing 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 speciffic 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-_ 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 ineVective anti-tumor immunological therapy to have a chance to be successful.