Abstract
Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.
Highlights
In the last few decades, immunotherapy has emerged as the fourth pillar following surgery, radiation/chemotherapy and targeted therapy for solid tumor and leukemia therapy
The results demonstrated that programmed death receptor-1 (PD-1) expression increased on both peripheral blood (PB) CD4+ (20.63% vs 15.86%, p=0.029) and CD8+ (24.77% vs 17.49%, p=0.011) T cells in de novo (DN) patients when compared with healthy individuls (HIs), while the same result was found when comparing the bone marrow (BM) CD4+ (26.17% vs 18.48%, p=0.010) and CD8+ (41.17% vs 21.68%, p=0.0003) T cell populations
When patients achieved complete remission (CR), we found that PD-1 expression recovered in most T cell populations except for the PB CD8+ population (27.00% vs 17.49%, p=0.014)
Summary
In the last few decades, immunotherapy has emerged as the fourth pillar following surgery, radiation/chemotherapy and targeted therapy for solid tumor and leukemia therapy. IC proteins are co-inhibitory receptors that distributed on the surface of several immune cells After ligand binding, these regulators can transducing inhibitory signals to avoid immune injury under physiological conditions. One of the features of T cell exhaustion is the occurrence of elevated expession of several IC proteins. When these proteins bind their ligands, they reduce the anti-virus or anti-tumor effects of T cells, resulting in the immune escape of pathogens or tumors [3, 6,7,8]
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