Differential Requirement for a Cellular Type-1 Immune Response in Tumor-Associated Versus Alloantigen-Targeted GvT Effects

Abstract

The major obstacles that impair successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies remain graft-versus-host disease (GvHD) and tumor relapse. Improved survival after allogeneic HSCT therefore requires more effective control of GvHD while preserving graft-versus-tumor (GvT) effects. Allogeneic parent-into-F1 murine transplant models (BALB/c or C57BL/6 --> F1[BALB/cxC57BL/6]) were used to evaluate the interrelation of GvHD and GvT effects targeting tumor-specific antigens or alloantigens on MethA tumor cells. Compared with syngeneic F1-into-F1 controls (F1[H-2(b/d)] --> F1: MethA[H-2d]), significant T cell-mediated GvT effects occurred in both allogeneic transplant models, even in the absence of histoincompatibilities between donor cells and host tumor (BALB/c[H-2d] --> F1: MethA[H-2d]). Selective inhibition of type-1 (Th-1/Tc1) immune responses with TAK-603 after HSCT nearly abolished GvHD in both allogeneic transplant models. While GvT effects directed against alloantigens (C57BL/6[H-2b] --> F1: MethA[H-2d]) remained unaffected during type-1-immune suppression, GvT effects targeted against tumor-associated antigens (BALB/c[H-2d] --> F1: MethA[H-2d]) were not evident. CONCLUSIONS.: Our data show that GvHD and GvT effects are in principle separable from each other by selective type-1 inhibition in transplantation models with major histocompatibility complex disparities between tumor, host, and donor. In contrast, in situations that only allow for GvT effects that exclusively target tumor-associated antigens (TAAs), type-1 inhibition results in complete abrogation not only of GvHD but also desired GvT reactions. These differences in GvT effects targeting alloantigens or TAAs and their interrelation to GvHD should be considered in future studies aimed at separating GvT reactions from GvHD.