Thymus Subset Alterations Accompanying Concomitant Tumor Immunity Mimics Phenotypic Patterns of Cytotoxic Drug Doxorubicin.

Abstract

Concomitant immunity (CIM) is a phenomenon that elicits an antitumor response not sufficient enough to destroy the primary tumor but prevents a secondary implant from growing and spreading. This study aimed to develop a method of identification of serum tumoricidal factors released into circulation during CIM and to compare the CIM-related effect to the effect elicited by the cytotoxic drug doxorubicin. SL2 tumor-bearing mice were studied at three time points - day 4, day 7, and day 11 following i.p. 5×105 cell implantation. Hematological effects and thymocyte immunophenotyping (CD4/CD8) data were compared to the effects induced by intravenous 10 mg/kg doxorubicin (DOX) administration to intact DBA 2 mice. The level of plasma colony stimulating factor-granulocyte macrophage (CSF-GM) was evaluated by ELISA. Identical thymus histopathology and an extent of double-positive CD4+CD8+ subset depletion was found in day 11 tumor-bearing mice (TBM-11) and in DOX-administered animals. TBM-11 exhibited a leukemoid reaction with an increase in monocyte and granulocyte counts. Conversely, DOX administration was followed by severe leukocytopenia at the 72-h time point. No increase in CSF-GM was observed in mice with or without a leukemoid reaction. The complexity of CIM can be examined by tracking alterations in the most fragile cortical CD8+CD4+ double positive population. Thymocyte apoptosis induced by DOX and TBM-11 might be associated with different mechanisms. TBM-11 did not exhibit severe myelotoxicity as DOX did. CIM-related serum factors can be assessed and screened via thymocyte subset analysis.