Page 59 - 2020_11-Haematologica-web

Basic biology of acute GvHD
and salvage therapy.99 In studies using Aza or decitabine treatment in the setting of blood cancers or myelodysplas- tic syndromes to reduce disease burden before transplanta- tion, there were no significant findings with regard to aGvHD.98,99 DNMT inhibitor treatment after allo-HSCT has typically been a component of salvage or maintenance therapy and has had some success in mitigating aGvHD. Ghobadi et al. treated patients with Aza after donor lym- phocyte infusion; no patients developed severe aGvHD (III-IV) and there was no aGvHD-caused mortality.95 Similarly, Schroeder et al. provided Aza treatment along- side donor lymphocyte infusion upon patients’ relapse and saw a 3.2-fold increase in Treg and a 1.9-fold increase in Treg frequency after four cycles of Aza treatment in patients who relapsed early after allo-HSCT.96 Goodyear et al. found that although the incidence of aGvHD was lower in treatment groups than in control groups, Treg increases in post-transplant acute myeloid leukemia patients were only observed within the first 3 months of treatment.97 These results suggest that early treatment may be required for a beneficial effect on aGvHD.
Because of its comparative success, it may be fruitful for future clinical trials to expand on the post-transplant, early HDAC inhibitor treatment paradigm. Of note, DNMT inhibitors were not typically used for aGvHD prevention, so patients often received other treatments (e.g., methotrexate) which were not standardized across studies.
EZH2 inhibitors
In vivo administration of GSK126 failed to reduce aGvHD and did not affect the development of alloreac- tive effector T cells in preclinical studies.33 This is in con- trast to observations that EZH2 deficiency led to aGvHD blockade in various murine allo-HSCT models.28 The mechanism of action of EZH2 in mediating aGvHD induction is therefore likely independent of its canonical target H3K27me3.33 Notably, EZH2 protein depletion by DZNep led to arrest of ongoing GvHD in experimental mice,30 indicating that targeting EZH2 may lead to new strategies to treat ongoing GvHD.
An interaction between HSP90 and EZH2 has also been shown to be vital for the stability and function of EZH2.33 A lack of HSP90 marks EZH2 for ubiquitination via the proteasome. Treatment of activated T cells with the HSP90 inhibitor AUY922 significantly decreased EZH2 protein levels while leaving histone methylation intact. HSP90 inhibitor treatment significantly decreased alloreactive T- cell responses and aGvHD in mice, affirming EZH2’s involvement in aGvHD pathogenesis and the non-canoni- cal hypothesis.33
The Food and Drug Administration has approved the EZH2 inhibitor tazemetostat specifically for the treat- ment of epithelioid sarcoma. We anticipate that this inhibitor may be used to target alloreactive memory T cells to reduce aGvHD in the future.
Future directions
As the epigenetics of aGvHD biology is a young area of study, there is much room for further investigation, both in elucidating mechanisms surrounding the action of known enzymes and in exploring the roles of new regu- lators documented here and beyond. Nevertheless, enor- mous progress has been made through the identification of critical enzymes and mechanisms. Next steps will be to further map how their pathways intersect amid the mul- titude of cell types and interactions that comprise aGvHD. Some epigenetic regulators (e.g., EZH2 and HDAC6) have points of commonality in their mecha- nisms of action (via HSP90).19,33,37 Advances will illuminate these locations of confluence such that more effective, integrated therapies may be developed. Additionally, a single regulator (e.g., HDAC11) may have beneficial or detrimental effects at different stages of cell development; understanding these situations will be vital for treatment. Also bringing promise for epigenetic intervention are those aspects of aGvHD pathogenesis that are T-cell- independent, such as microbiome injury.
Different tissues, hematopoietic and non-hematopoiet- ic, have distinct roles in mediating aGvHD immunopathology. Further investigation of the epigenet- ics surrounding the role of non-hematopoietic APC would likely be beneficial for the field. In addition, tissue- intrinsic mechanisms that contribute to inhibition of aGvHD have been somewhat overlooked. These include those controlling tissue regeneration,81-83 and those modu- lating tissue-resident APC, which are critical for local aGvHD induction.100 Furthermore, aGvHD blocks periph- eral tolerance of host-reactive T cells by elimination of lymph node fibroblastic reticular cells that induce T-cell tolerance in the gut.101 Thus, future studies should also investigate the epigenetic mechanisms that regulate tis- sue regeneration and regulation of the graft-versus-host reaction, as suggested by Reddy and colleagues.91
Acknowledgments
This study was supported by grants from the NCI (CA172106-01, YZ), NHLBI (HL127351-01A1, YZ) and NIAID (AI143256-01A1, YZ).
References
1. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167- 2179.
2.Koyama M, Kuns RD, Olver SD, et al. Recipient nonhematopoietic antigen-pre- senting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med. 2011;18(1):135-142.
3. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells.
Science. 1999;285(5426):412-415.
4. Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG. Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-medi- ated acute graft-versus-host disease. J Clin
Invest. 2002;109(10):1335-1344.
5.Chung J, Ebens CL, Perkey E, et al.
Fibroblastic niches prime T cell alloimmuni- ty through Delta-like Notch ligands. J Clin Invest. 2017;127(4):1574-1588.
6. Koyama M, Mukhopadhyay P, Schuster IS, et al. MHC class II antigen presentation by the intestinal epithelium initiates graft-ver- sus-host disease and is influenced by the microbiota. Immunity. 2019;51(5):885-
898.e7.
7. Wu CJ, Ritz J. Induction of tumor immunity
following allogeneic stem cell transplanta-
tion. Adv Immunol. 2006;90:133-173.
8. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med.
2005;11(12):1299-1305.
9. Zhang Y, Joe G, Hexner E, Zhu J, Emerson
SG. Alloreactive memory T cells are respon- sible for the persistence of graft-versus-host disease. J Immunol. 2005;174(5):3051-3058.
10. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implica- tions for vaccine development. Nat Rev
haematologica | 2020; 105(11)
2547