Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity
Simone A. Minnie, Olivia G. Waltner, Kathleen S. Ensbey, Nicole S Nemychenkov, Christine R. Schmidt, Shruti S. Bhise, Samuel R.W. Legg, Gabriela Campoy, Luke Samson, Rachel D. Kuns, Ting Zhou, John D. Huck, Slavica Vučković, Danniel Zamora, Albert C. Yeh, Andrew Spencer, Motoko Koyama, Kate A. Markey, Steven Lane, Michael Boeckh, Aaron M. Ring, Scott N. Furlan, Geoffrey R. Hill
Abstract
Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects. We found that CD8 + T cell exhaustion in bone marrow was primarily alloantigen-driven, with expression of inhibitory ligands present on myeloma but not AML. Because of this tumor-independent exhaustion signature, immune checkpoint inhibition (ICI) in myeloma exacerbated graft-versus-host disease (GVHD) without promoting GVT effects. Administration of post-transplant cyclophosphamide (PT-Cy) depleted donor T cells with an exhausted phenotype and spared T cells displaying a stem-like memory phenotype with chromatin accessibility present in cytokine signaling genes, including the interleukin-18 (IL-18) receptor. Whereas ICI with anti–PD-1 or anti–TIM-3 remained ineffective after PT-Cy, administration of a decoy-resistant IL-18 (DR-18) strongly enhanced GVT effects in both myeloma and leukemia models, without exacerbation of GVHD. We thus defined mechanisms of resistance to T cell–mediated antitumor effects after alloBMT and described an immunotherapy approach targeting stem-like memory T cells to enhance antitumor immunity.