Abstract
Background: There are several ways for malignant cells to increase their number. One of them is to use immune checkpoints protecting malignant cells from immune-mediated injury. Upregulation of immune checkpoints contributes immune escape and tumor growth. Tyrosine kinase inhibitors (TKI) have improved the outcome of chronic myeloid leukemia (CML). TKI is generally known to inhibit the target BCR-ABL1 kinase in leukemic cells. However, constantly growing evidence suggests that some TKIs activate the immune system to exert the direct cytotoxic effects. In this study, we evaluated expression levels of PD-1 on T-cells in CML patients, and found the relation with ABL kinase mutation. We analyzed the relation between the quantitative levels of BCR-ABL and PD-1 expression percentages.
Methods: We obtained 82 bone marrow (BM) samples from patients diagnosed as CML at Asan medical center in Korea between May 2016 and May 2017. The samples included 22 at diagnosis (20 in chronic phase; CP and 2 in blast phase; BP) and 60 at follow-up (52 in complete hematologic remission; CHR, 1 in CP, 1 in accelerated phase; AP, and 6 in BP). All patients at follow-up were treated with Imatinib, Dasatinib, Nilotinib and/or Radotinib. Normal BM samples were collected from 23 individuals with no evidence of hematologic malignancies as the controls. Expression of PD-1 on T cells was measured using flow cytometric analysis.
Results: The median expression level of PD-1 on CD8+ T cells for the patients in CHR was 21.25%, which was significantly lower than those in controls, in CP and in BP (Fig. 1). At diagnosis of CML, the median expression level of PD-1 on CD8+ T cells was 34.7%. In CML patients treated with Imatinib and/or dasatinib, the expression levels of PD-1 on CD8+ T cells were lower than at diagnosis (respectively, P < 0.001 and P= 0.045). In CML patients treated with Nilotinib, there was no difference of expression levels of PD-1 compared with those at diagnosis. In CML patients with ABL kinase mutation, the expression levels of PD-1 on CD8+ T cells was much higher than those of CML patients without ABL kinase mutation group (P= 0.008) (Fig. 2). The level of PD-1 expression positively correlated with the quantitative levels of BCR/ABL detected by RT-PCR in BM (P= 0.024, rho = 0.270). We found 2 patients who had more than 4 follow-up data over a 6 month-period and serialized the changes of BCR/ABL quantitation, PD-1 expression percentages on CD8+ T cells and disease phases of them. PD-1 expression percentages seemed to reflect the progression of the diseases, based on very limited data (Fig. 3).
Conclusion: The low expression PD-1 on CD8+ T cells might play a role in maintaining CHR in CML. The high expression of PD-1 expression in CML patients with ABL kinase mutation demonstrated that TKI had the effect of lowering the expression of PD-1 on CD8+ T cells. We conclude that PD-1 on CD8+ T cells could be important to control CML, and the immune checkpoint inhibitors might be effective in CML patients, particularly those with ABL kinase mutation.
Lee: Boehringer Ingelheim: Research Funding.
