Mechanisms of immune escape after allogeneic hematopoietic cell transplantation

Relapse of the original disease is a major cause of death after allogeneic hematopoietic cell transplantation for acute leukemias. There is growing evidence that relapses may be explained not only by resistance to chemotherapy but also by the escape of tumor cells from the control of the allogeneic immune response. Mechanisms of immune evasion can involve abrogation of leukemia cell recognition due to loss of HLA genes, immunosuppression by immune-checkpoint ligand expression, production of anti-inflammatory factors, release of metabolically active enzymes, loss of proinflammatory cytokine production, and acquisition of novel driver mutations that promote leukemia outgrowth. These mechanisms, and therapeutic targeting of immune escape, will be discussed. We divide the evidence in support of immune-escape mechanisms into animal studies, human laboratory studies, and human clinical experience. A better understanding of the molecular pathways connected to immune escape and relapse may help to improve our therapeutic armamentarium against acute myeloid leukemia relapse.