PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

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.

Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology

“…Our observations of immune status in the untreated AML patients were consistent with increased lymphocyte exhaustion, as previously reported [13][14][15], including enhanced PD-1 immune checkpoint expression [34], decreased DNAM-1 activating receptor expression on NK cells [35], and potent upregulation of the exhaustion and immunosuppressive marker CD39 on B, NK, and CD4 + T lymphocytes. Our findings revealed a shift to more mature lymphocyte differentiation in patients with decreased CD27 expression by T cells and increased CD57 expression on NK cells.…”

Dynamics of PD-1 expression are associated with treatment efficacy and prognosis in patients with intermediate/high-risk myelodysplastic syndromes under hypomethylating treatment

“…Isotype-matched antibodies, labeled with the proper fluorochromes, were used as negative controls. Cells were analyzed using a BD Fortessa flow cytometer (BD Biosciences), and data analysis was performed with Flowjo 10.6 software as previously described ( 22 ).…”

The cytokine network in acute myeloid leukemia

“…Indeed, high expression of PD-L1 and PD-L2 is associated with poor OS in AML patients ( 173 , 174 ). Binding of PD-L1/PD-L2 to the receptor PD-1 increases T cell exhaustion, promotes effector T cell apoptosis, induces the resistance to effector T cell-mediated killing ( 175 ) and increases the conversion and development of Tregs which have strong immune-suppressive abilities ( 176 ). Thus, the potential induction of PD-L1 and PD-L2 by IFN-γ may have unfavorable consequences, because the PD-1/PD-L1/PD-L2 axis helps the tumor to maintain an immunosuppressive microenvironment, thereby promoting immune evasion and survival of cancer cells ( 177 ).…”