T-cell reconstitution by molecular, phenotypic, and functional analysis in the thymus, bone marrow, spleen, and blood following split-dose polychemotherapy and therapeutic activity for metastatic breast cancer in mice

Abstract

We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) on neutrophil and lymphocyte subpopulations in the peripheral blood leukocytes (PBLs), thymus, bone marrow, and spleen. It was found that this protocol of polychemotherapy, modeled after the induction protocol used with autologous bone marrow transplantation (AuBMT) for breast cancer, suppressed both B- and T-cell populations and T-cell function at times when the absolute neutrophil count had returned to normal or supernormal numbers. We observed an organ- and phenotype-specific T- and B-cell recovery to normal levels following chemotherapy. However, despite normalization of cellularity and phenotype frequency, splenic lymphocytes remained unable to respond to normally concanavalin A (ConA). This polychemotherapy protocol in mice with an extensive experimental metastasis mammary tumor burden, was a dose lethal to 20% of the test group, which could be overcome with treatment by BMT and rHu interleukin (IL)-7. Furthermore, therapy with the T-cell augmenting agent rHu IL-7 had additive therapeutic activity and significantly prolonged survival beyond that of chemotherapy and BMT although it did not cure any mice with a heavy tumor burden. In summary, these studies demonstrate an organ-specific and selective polymorphonuclear neutrophil and T- and B-cell reconstitution following multidrug, split-dose chemotherapy on tissue and PBL populations, and a chronic depression in T-cell function, which when modified can result in significant therapeutic activity.