Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML
Tóm tắt
Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome. PB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry. The proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy. Upregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.
Tài liệu tham khảo
Beyar-Katz O, Gill S. Novel approaches to acute myeloid leukemia immunotherapy. Clin Cancer Res. 2018;24(22):5502–15.
Wang M, Bu J, Zhou M, Sido J, Lin Y, Liu G, et al. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. Clin Immunol. 2018;190:64–73.
Yang X, Wang J. Precision therapy for acute myeloid leukemia. J Hematol Oncol. 2018;11(1):3.
Chisini M, Stefanizzi C, Ceglie T, Raponi S, Vozella F, Colafigli G, et al. Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia. Hematol Oncol. 2017;35(4):804–9.
Yu B, Liu D. Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia. Biomark Res. 2019;7:24.
Gu R, Yang X, Wei H. Molecular landscape and targeted therapy of acute myeloid leukemia. Biomark Res. 2018;6:32.
Kasakovski D, Xu L, Li Y. T cell senescence and CAR-T cell exhaustion in hematological malignancies. J Hematol Oncol. 2018;11(1):91.
Xu L, Yao D, Tan J, He Z, Yu Z, Chen J, et al. Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia. J Hematol Oncol. 2018;11(1):93.
Yao D, Xu L, Tan J, Zhang Y, Lu S, Li M, et al. Re-balance of memory T cell subsets in peripheral blood from patients with CML after TKI treatment. Oncotarget. 2017;8(47):81852–9.
Sun HF, Wei S, Yang LL. Dysfunction of immune system in the development of large granular lymphocyte leukemia. Hematology. 2019;24(1):139–47.
Huang J, Tan J, Chen Y, Huang S, Xu L, Zhang Y, et al. A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia. J Leukoc Biol. 2019;106(3):725–32.
Yang Y, Kohler ME, Chien CD, Sauter CT, Jacoby E, Yan C, et al. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med. 2017;9(417):eaag1209.
Huang X, Yang Y. Driving an improved CAR for cancer immunotherapy. J Clin Invest. 2016;126(8):2795–8.
Zhang Y, Li Y. T cell receptor-engineered T cells for leukemia immunotherapy. Cancer Cell Int. 2019;19:2.
Porter DL. Advances in CAR T-cell therapy for chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2018;16(2):118–20.
Daver N, Boddu P, Garcia-Manero G, Yadav SS, Sharma P, Allison J, et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. 2018;32(5):1094–105.
Davis KL, Agarwal AM, Verma AR. Checkpoint inhibition in pediatric hematologic malignancies. Pediatr Hematol Oncol. 2017;34(6–7):379–94.
Silva IG, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. Ebiomedicine. 2017;22:44–57.
Alfayez M, Borthakur G. Checkpoint inhibitors and acute myelogenous leukemia: promises and challenges. Expert Rev Hematol. 2018;11(5):373–89.
Tan J, Chen S, Lu Y, Yao D, Xu L, Zhang Y, et al. Higher PD-1 expression concurrent with exhausted CD8+ T cells in patients with de novo acute myeloid leukemia. Chin J Cancer Res. 2017;29(5):463–70.
Williams P, Basu S, Garcia-Manero G, Hourigan CS, Oetjen KA, Cortes JE, et al. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer. 2019;125(9):1470–81.
Chen Y, Tan J, Huang S, Huang X, Huang J, Chen J, et al. Higher frequency of the CTLA-4(+) LAG-3(+) T-cell subset in patients with newly diagnosed acute myeloid leukemia. Asia Pac J Clin Oncol. 2019. https://doi.org/10.1111/ajco.13236.
Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116(14):2484–93.
Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501–10.
Roth CG, Garner K, Eyck ST, Boyiadzis M, Kane LP, Craig FE. TIM3 expression by leukemic and non-leukemic myeloblasts. Cytometry B Clin Cytom. 2013;84(3):167–72.
Kikushige Y, Akashi K. TIM-3 as a therapeutic target for malignant stem cells in acute myelogenous leukemia. Ann N Y Acad Sci. 2012;1266:118–23.
Zahran AM, Saleh MFM, Sayed MM, Rayan A, Ali AM, Hetta HF. Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia. Cancer Biomark. 2018;22(3):587–95.
Jia B, Wang LR, Claxton DF, Ehmann WC, Rybka WB, Mineishi S, et al. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients. Blood Cancer J. 2018;8(34):1265.
Chen XY, Cherian S. Acute myeloid leukemia Immunophenotyping by flow Cytometric analysis. Clin Lab Med. 2017;37(4):753.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.
Zhang QY, Dai KC, Bi LX, Jiang SF, Han YX, Yu K, et al. Pretreatment platelet count predicts survival outcome of patients with de novo non-M3 acute myeloid leukemia. Peer J. 2017;5:e4139.
Tan JX, Chen SH, Huang JY, Chen YC, Yang LJ, Wang CL, et al. Increased exhausted CD8(+) T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma. Asia-Pac J Clin Oncol. 2018;14(5):e266–74.
Di Rosa F, Gebhardt T. Bone marrow T cells and the integrated functions of recirculating and tissue-resident memory T cells. Front Immunol. 2016;7:51.
Liu XD, Jiang S, Zhang Q, Xu SM, Bao XW, Cao W, et al. Tim-3 regulates Tregs’ ability to resolve the inflammation and proliferation of acute lung injury by modulating macrophages polarization. Shock. 2018;50(4):455–64.
Duan JJ, Wang Y, Jiao SC. Checkpoint blockade-based immunotherapy in the context of tumor microenvironment: opportunities and challenges. Cancer Med-Us. 2018;7(9):4517–29.
Li CX, Chen XC, Yu X, Zhu YB, Ma C, Xia R, et al. Tim-3 is highly expressed in T cells in acute myeloid leukemia and associated with clinicopathological prognostic stratification. Int J Clin Exp Patho. 2014;7(10):6880–8.