Good or bad cops: immune cells in aGVHD

In this issue of Blood, van Halteren et al have identified an immune cell signature associated with the onset of acute graft-versus-host disease (aGVHD) and with the treatment response to first- and second-line therapy.¹ 

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for many advanced hematopoietic malignant diseases. Its success in curing these disorders relies on the synergistic effect of eradicating malignant host leukocytes by pretransplant treatment regimens, such as chemotherapy and radiation, and full reconstitution of a donor-derived immune system mediating posttransplant graft-versus-leukemia effect (GvL) against remaining malignant cells.^2,3 Alongside desired GvL, unwanted acute GVHD may result from complex interaction of tissue-resident host immune cells and newly engrafted donor cells.^4,5 Acute GVHD is a major complication of HSCT that limits its broader application. Despite significant progress in prophylactic and therapeutic strategies, GVHD remains a major cause of morbidity and mortality after HSCT, occurring after 30% to 40% of transplants and accounting for up to 15% of deaths. Remarkably, relapse rates are significantly lower in patients who develop GVHD,⁶ indicating a link between GVHD and GvL.

For decades, high dosages of glucocorticosteroids such as prednisone or methylprednisolone have remained a pillar of frontline treatment in HSCT recipients who develop grade 2 to 4 GVHD, despite GVHD prophylaxis. The broad immunosuppression induced by glucocorticosteroids is associated with severe side effects. GVHD is not resolved in roughly half of the patients receiving such treatment, and their disease is considered steroid refractory (SR-GVHD). Additional treatment options exist today, with JAK inhibition, tumor necrosis factor blockade, extracorporeal photosynthesis, or mesenchymal stem cells being used as second-line therapy.^7,8 Nevertheless, overall survival in SR-GVHD is less than 50% at 6 months, and overall survival in response to second-line therapies is also poor (<30%).⁸ 

The underlying mechanisms accounting for SR-GVHD and biomarkers associated with response to therapy are currently unknown. Therefore, it is important to identify mechanisms underlying GVHD development and clinical response to glucocorticosteroids and second-line therapies. In addition, the identification of markers that predict individual patient response to first- and second-line therapy will be crucial to implementation of personalized targeted treatment.

van Halteren et al analyzed patient cohorts that were defined by their response to therapy. By doing so, they found in a broad analysis using mass cytometry that various immune cell compartments were changed even prior onset of clinical symptoms at early stages of aGVHD. By applying high-dimensional CYTOF profiling (an application of mass cytometry in which antibodies are labeled with heavy metal ion tags rather than fluorochromes) of blood samples of aGVHD patients, the authors found higher numbers of CD163⁺CD11b⁺ monocytes and T-cell subsets expressing skin- and gut-homing molecules in the peripheral blood of aGVHD patients even before there were clinical manifestations of the disease. When examining aGVHD cohorts with different responses to first- and second-line therapy by mass cytometry, the authors found higher numbers of effector and regulatory T cells with skin- and gastrointestinal-homing receptors, certain dendritic cell subsets, and plasmablasts to be associated with therapy refractory GVHD (see figure). Importantly, findings in peripheral blood samples were corroborated with tissue samples of gastrointestinal tract or skin affected by GVHD. As the sample size of the different patient cohorts was rather small in the present study, validation will be needed to assess the utility and reproducibility of the findings for use as prognostic markers for treatment response. Equally important, this study identifies the contributions of several immune cell compartments to SR-GVHD. Uncovering the cellular interactions between T cells, dendritic cells, and B cells that contribute to treatment response will be quite important. The unique approach of high-dimensional immune cell profiling in well-defined patient cohorts will provide new perspectives of the immune cell network in complex diseases in future well beyond the specific context of GVHD.

Conflict-of-interest disclosure: The author declares no competing financial interests.