T cell-macrophage crosstalk in GVHD and cancer immunotherapy

The immune microenvironment is pivotal in regulating two complementary adverse outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT): graft-versus-host disease (GVHD) and tumor progression. While GVHD manifests as immune hyperactivation, causing tissue injury, cancer subverts immune surveillance by immunosuppressive strategies. Although initial studies focused on distinct mechanisms involving T-B interactions in GVHD and T-tumor cell interactions in cancer immunotherapy, it is increasingly clear that dysregulated T cell-macrophage interactions drive immunopathology in GVHD, with comparative insights into cancer immunotherapy. Here, we discuss recent advances and elucidate three core regulatory paradigms governing these immunostimulatory vs immunosuppressive interactions: (1) cytokine networks, (2) immune checkpoint regulation, and (3) metabolic reprogramming. Based on functional pre-clinical studies and clinical evidence, we describe the dynamic, reciprocal immune crosstalk between T cells and macrophages that underlies GVHD after allo-HSCT and the immunosuppressive tumor microenvironment. Finally, we outline emerging therapeutic approaches that target T cell and macrophage interactions to prevent GVHD and overcome an immunologically “cold” microenvironment in the cancer.