Graft-Versus-Tumor (GvT) Effects in the Absence of Alloantigens on Tumor Cells Crucially Depend on Graft-Versus-Host Disease (GvHD) Intensity.
Authors: Albring Jörn C. , Stelljes Matthias , Berdel Wolfgang E. , Kienast Joachim 
Published: April 2020

Abstract
While a variety of tumors is potentially immunogenic and is capable to trigger tumor-associated antigen (TAA)-specific immune responses in vivo the endogenous immune system usually fails to eradicate established tumors. Despite considerable effort and promising experimental and preliminary clinical data most cellular immunotherapeutic strategies have not evolved into a clinically relevant treatment strategy with allogeneic immune replacement as cancer immunotherapy being the sole exception. At this juncture allogeneic HSCT not only allows for otherwise fatal high-dose chemo- and radiotherapy intended to reduce the tumor cell burden but also encompasses potent immunologically mediated anti-tumor effects, referred to as GvT reaction. This GvT reaction, which is based on donor T and natural killer cells, is interrelated, however, with potentially deleterious GvHD, one of the major limitations of allogeneic HSCT. Mutated tumor-associated antigens, as well as selectively or aberrantly expressed nonmutated antigens, represent potential targets for T cell-mediated GvT effects that are in principle, separable from generalized anti-host responses. Using an allogeneic parent-into-F1 murine transplantation model (BALB/c or C57BL/6 → [C57BL/6 x BALB/c]F1) with different chemically induced tumors derived from either parental strain, we have previously demonstrated that a significant CD8+ T cell-mediated GvT effect accounts for immunological tumor control after allogeneic HSCT in vivo. Remarkably, this effect occurs in the absence of histoincompatibilities between donor immune cells and host tumor (Blood2004; 104:1210–1216). Since most chemically induced tumors have immunogeneic neo-antigens we sought to expand our initial findings to spontaneously occurring tumor cell lines, which often are less immunogenic. In addition, we asked whether the intensity of GvHD directly impacts on GvT effects in the absence of alloantigens on tumor cells. Sublethally irradiated [C57BL/6 x BALB/c]F1 (H-2b/d) mice were transplanted with whole bone marrow with or without splenocytes from allogeneic C57BL/6 (H-2b) and BALB/c (H-2d) donors, respectively. Recipient mice were inoculated subcutaneously with hematological and solid tumors derived from either C57BL/6 (B16, LLC - both H-2b) or BALB/c (RENCA, A20, MPC-11, WEHI-3B - all H-2d) strains. By varying the histocompatibility between donor immune cells, host tissue and tumor tissue, it was possible to study GvT effects in the absence of alloantigens on tumor cells. Furthermore, using different numbers of coinjected donor splenocytes the interrelation of GvHD intensity and alloantigen independent GVT effects was assessed. As compared with allograft recipients having weak GvHD (2x107 bone marrow cells) a significant tumor-alloantigen independent GvT effect was present in animals undergoing intense GvHD (2x107 bone marrow cells and 107 splenocytes). These data indicate that a biologically relevant GvT effect that is independent of alloantigen recognition on tumor cells is crucially influenced by the intensity of GvHD.