Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity.
Transgenic female mice expressing the transforming rat oncogene c-erbB-2 (HER-2/neu) under the mouse mammary tumor virus (MMTV) promoter (BALB-neuT) spontaneously develop mammary carcinomas with a progression resembling that of human breast cancer. In these mice, activating antitumor immunotherapy fails to induce T cell-mediated cytotoxicity, suggesting a suppression of the immune response. We found a direct correlation between tumor multiplicity and an increased proportion of Gr-1+ (Ly6G)/Mac-1+(CD11b)/ER-MP12+(CD31) immature myeloid cells in the peripheral blood (PB) and spleen, suggesting that tumor load profoundly affects overall BALB-neuT hematopoiesis. In fact, myeloid colony formation was increased in bone marrow (BM) and spleen. The immature myeloid cells displayed suppressive activity on host T lymphocytes, which progressively failed to respond to alloantigens and CD3 triggering, while maintaining the ability to proliferate in response to nonspecific mitogens. Transplantation of normal BM into BALB-neuT mice readily resulted in hypertrophic hematopoiesis with myeloid cell expansion. This persistent influence of the tumor was mediated through the release of vascular endothelial growth factor (VEGF) but not granulocyte-macrophage colony-stimulating factor (GM-CSF), and was down-modulated when tumor load was reduced but not when BM was transplanted. Together, the data obtained in the BALB-neuT model of naturally occurring carcinogenesis show that tumor-associated immune suppression is secondary to a more general alteration of host hematopoiesis, conditioned by tumor-secreted soluble factors.
Immunotherapy and Gene Therapy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, via G. Venezian 1, 20133 Milan, Italy. melani@istitutotumori.mi.it
Cecilia
C
Melani
Claudia
C
Chiodoni
Guido
G
Forni
Mario P
MP
Colombo
D000818:Animals; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D006410:Hematopoiesis / Q000502:physiology; D007108:Immune Tolerance / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000503:physiopathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000737:chemistry / Q000166:cytology*; D011401:Promoter Regions, Genetic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013154:Spleen / Q000166:cytology
D015415:Biomarkers; D016177:Macrophage-1 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases