Graft versus tumor effects and why people relapse

Abstract

Graft-versus-tumor (GVT) reactivity mediated by donor T cells in the context of allogeneic stem cell transplantation (alloSCT) is one of the most potent forms of cellular immunotherapy. The antitumor effect against hematologic malignancies is mediated by a polyclonal T-cell response targeting polymorphic antigens expressed on hematopoietic tissues of the recipient, leaving donor hematopoiesis in the patient after transplantation unharmed. Fortunately, hematopoietic tissues (including malignant hematopoietic cell populations) are relatively susceptible to T-cell recognition. If, however, nonhematopoietic tissues of the recipient are targeted as well, graft-versus-host disease (GVHD) will occur. The balance between GVT and GVHD is influenced by the genetic disparity between donor and recipient, the number and origin of professional antigen-presenting cells provoking the immune response, the target antigen specificity, magnitude and diversity of the response, and the in vivo inflammatory environment, whereas inhibitory factors may silence the immune response. Manipulation of each of these factors will determine the balance between GVT and GVHD.

Figure 1.

Peptide/HLA complexes as targets of T cell–mediated alloimmune reactivity. (A) Self peptides expressed in self HLA molecules induce tolerance. (B) Polymorphic nonself peptides recognized in the context of self HLA molecules can induce alloreactivity; these polymorphic nonself peptides are called minor histocompatibility antigens (MiHA). (C) Monomorphic (self) peptides presented in the context of nonself HLA molecules provoke alloreactivity. (D) Polymorphic nonself peptides in the context of nonself HLA molecules can also provoke alloreactivity.

Figure 2.

GVT and GVHD targets in alloreactivity. (A) Donor and recipient are fully HLA identical. Polymorphic nonself peptides (MiHA) selectively expressed on hematopoietic cells provoke hematopoiesis-specific GVT responses. Polymorphic nonself peptides (MiHA) derived from broadly expressed genes can provoke combined GVT and GVHD. (B) CD8 T cells recognizing peptides presented in the context of nonself HLA class I molecules can mediate combined GVT and GVHD reactivity. CD4 T cells recognizing peptides in the context of HLA class II molecules mediate specific GVT responses under noninflammatory circumstances when HLA class II molecules are not expressed on nonhematopoietic tissues. Under inflammatory circumstances, upregulation of HLA class II on nonhematopoietic tissues causes combined GVT and GVHD by alloreactive CD4 T cells.

Figure 3.

Balance between GVT and GVHD after T cell–replete or T cell–depleted transplantation. (A) T cell–replete alloSCT: conditioning regimen induced tissue damage and pathogens mediate activation of recipient APC, lymphopenia-associated homeostatic proliferation, and an inflammatory cytokine milieu resulting in highly diverse and high-magnitude alloimmune T-cell responses causing simultaneous GVT and GVHD reactivity, requiring posttransplant immune suppression. (B) T-cell depletion abrogates GVT and GVHD early after transplantation, resulting in an increased risk of relapse and lack of control of pathogens. Postponed donor T-cell infusions (donor lymphocyte infusion [DLI]) are needed for GVT reactivity: the risk of GVHD is lower due to tissue repair, less inflammation, and replacement of recipient APC by donor APC.