Increased expression of immune checkpoint programmed cell death protein-1 (PD-1) on T cell subsets of bone marrow aspirates in patients with B-Lymphoblastic leukemia, especially in relapse and at diagnosis.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 101235690 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4957 (Electronic) Linking ISSN: 15524949 NLM ISO Abbreviation: Cytometry B Clin Cytom Subsets: MEDLINE

Original Publication: Hoboken, N.J. : Wiley-Liss, c2002-

B7-H1 Antigen/*genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Programmed Cell Death 1 Ligand 2 Protein/*genetics ; Programmed Cell Death 1 Receptor/*genetics; Adult ; Apoptosis Regulatory Proteins/immunology ; B7-H1 Antigen/immunology ; CD8-Positive T-Lymphocytes/immunology ; Female ; Flow Cytometry ; Gene Expression Regulation, Leukemic/genetics ; Humans ; Immune Checkpoint Inhibitors/immunology ; Immune Checkpoint Inhibitors/therapeutic use ; Male ; Middle Aged ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Programmed Cell Death 1 Ligand 2 Protein/immunology ; Programmed Cell Death 1 Receptor/immunology ; Recurrence ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/pathology

Background: We analyzed expression profiles of immune checkpoint receptors on T cell subsets and ligands on leukemic blasts in patients with B-lymphoblastic leukemia (B-ALL).
Methods: Total 149 bone marrow (BM) samples obtained from 65 B-ALL patients with four different clinical status (41 at diagnosis, 54 in complete remission [CR], 34 in persistence, and 20 in relapse), and 32 BM control samples were prospectively enrolled. Expression of immune checkpoint receptor (programmed cell death protein-1 [PD-1]) on T cell subsets and ligands (PD-L1, PD-L2) on leukemic blasts was evaluated by flow cytometry, and was compared between patient subgroups.
Results: Relapsed patients demonstrated highest PD-1 expression proportion and intensity on CD3 ⁺ CD4 ⁺ T cells with statistical significance when compared to patients in persistence/CR/BM controls (p = .027/<.001/<.001 and .012/.001/<.001, respectively). Newly diagnosed patients showed significantly lower PD-1 expression proportion on CD3 ⁺ CD4 ⁺ T cells than relapsed patients (p < .001), but their intensity was not significantly different. Relapsed patients showed significantly higher PD-1 expression proportion and intensity on CD3 ⁺ CD8 ⁺ T cells than patients in CR/BM controls (p = .022/.045 and .049/.005, respectively), but PD-1 expression status on them were not significantly different between relapsed and newly diagnosed patients. PD-L1/L2 expression on leukemic blasts was not significantly different between patient subgroups.
Conclusions: In BM aspirates from B-ALL patients, PD-1 expression on T-cell subsets is increased at diagnosis, and to a greater extent, at relapse. These data suggest the potential usefulness of PD-1 blockade in the treatment of B-ALL, particularly at relapse.
(© 2020 International Clinical Cytometry Society.)

Albring, J. C., Inselmann, S., Sauer, T., Schliemann, C., Altvater, B., Kailayangiri, S., … Stelljes, M. (2017). PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation. Bone Marrow Transplantation, 52(2), 317-320.
Ansell, S. M., Lesokhin, A. M., Borrello, I., Halwani, A., Scott, E. C., Gutierrez, M., … Armand, P. (2015). PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England Journal of Medicine, 372(4), 311-319.
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., … Brahmer, J. R. (2015). Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. The New England Journal of Medicine, 373(17), 1627-1639.
Brahmer, J., Reckamp, K. L., Baas, P., Crinò, L., Eberhardt, W. E., Poddubskaya, E., … Spigel, D. R. (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. The New England Journal of Medicine, 373(2), 123-135.
Chen, X., Liu, S., Wang, L., Zhang, W., Ji, Y., & Ma, X. (2008). Clinical significance of B7-H1 (PD-L1) expression in human acute leukemia. Cancer Biology & Therapy, 7(5), 622-627.
Daver, N., Basu, S., Garcia-Manero, G., Cortes, J. E., Ravandi, F., Jabbour, E. J., … Sharma, P. (2016). Phase IB/II study of Nivolumab in combination with Azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). Blood, 128(22), 763.
Davids, M. S., Kim, H. T., Bachireddy, P., Costello, C., Liguori, R., Savell, A., … Leukemia and Lymphoma Society Blood Cancer Research Partnership. (2016). Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med, 375(2), 143-153.
Dubey, C., Croft, M., & Swain, S. L. (1996). Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. Journal of Immunology, 157(8), 3280-3289.
Ferris, R. L., Blumenschein, G., Jr., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., … Gillison, M. L. (2016). Nivolumab for recurrent squamous-cell carcinoma of the head and neck. The New England Journal of Medicine, 375(19), 1856-1867.
Feucht, J., Kayser, S., Gorodezki, D., Hamieh, M., Döring, M., Blaeschke, F., … Feuchtinger, T. (2016). T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget, 7(47), 76902-76919.
Garcia-Manero G, Daver NG, Montalban-Bravo G, Jabbour EJ, DiNardo CD, Kornblau SM, Bose P, Alvarado Y, Ohanian M, Borthakur G, Cortes JE, Naqvi K, Pemmaraju N, Huang X, Nogueras-Gonzalez GM, Bueso-Ramos CE, Gasior Y, Bayer VR, Pierce S, Yang H, Colla S, Kantarjian HM. A phase II study evaluating the combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in pts with previously treated or untreated myelodysplastic syndromes (MDS). Blood 2016;128(22):344. Accessed June 30, 2019. Retrieved from http://www.bloodjournal.org/content/128/22/344.
Herbaux, C., Gauthier, J., Brice, P., Drumez, E., Ysebaert, L., Doyen, H., … Morschhauser, F. (2017). Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood, 129(18), 2471-2478.
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., … Urba, W. J. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine, 363(8), 711-723.
Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., … Ahmed, R. (2017). Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science, 355(6332), 1423-1427.
Kong, Y., Zhang, J., Claxton, D. F., Ehmann, W. C., Rybka, W. B., Zhu, L., … Zheng, H. (2015). PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation [serial online]. Blood Cancer Journal, 5, e330.
Lim, S. N., Joo, Y. D., Lee, K. H., Kim, D. Y., Lee, J. H., Lee, J. H., … Jang, D. Y. (2015). Long-term follow-up of imatinib plus combination chemotherapy in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. American Journal of Hematology, 90(11), 1013-1020.
Linker, C., Damon, L., Ries, C., & Navarro, W. (2002). Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. Journal of Clinical Oncology, 20(10), 2464-2471.
Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 12(4), 252-264.
Park, S. H., Lee, M. J., Park, C. J., Jang, S., Seo, E. J., Im, H. J., & Seo, J. J. (2019). Bone marrow recovery of hematopoietic stem cells and microenvironment after chemotherapy in childhood acute lymphoblastic leukemia: Consecutive observations according to chemotherapy schedule. Pediatric Hematology and Oncology, 36(4), 222-235.
Schnorfeil, F. M., Lichtenegger, F. S., Emmerig, K., Schlueter, M., Neitz, J. S., Draenert, R., … Subklewe, M. (2015). T cells are functionally not impaired in AML: Increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. Journal of Hematology & Oncology, 8, 93.
Tan, J., Chen, S., Huang, J., Chen, Y., Yang, L., Wang, C., … Li, Y. (2018). Increased exhausted CD8+ T cells with programmed death-1, T-cell immunoglobulin and mucin-domain-containing-3 phenotype in patients with multiple myeloma. Asia-Pacific Journal of Clinical Oncology, 14(5), e266-e274.
Tan, J., Chen, S., Lu, Y., Yao, D., Xu, L., Zhang, Y., … Li, Y. (2017). Higher PD-1 expression concurrent with exhausted CD8+ T cells in patients with de novo acute myeloid leukemia. Chinese Journal of Cancer Research, 29(5), 463-470.
Tan, J., Huang, S., Huang, J., Yu, Z., Chen, Y., Lu, Y., … Chen, S. (2020). Increasing Tim-3+CD244+, Tim-3+CD57+, and Tim-3+PD-1+ T cells in patients with acute myeloid leukemia. Asia-Pacific Journal of Clinical Oncology. 2020, 1-5. https://doi.org/10.1111/ajco.13304 [Epub ahead of print].
Tan, J., Yu, Z., Huang, J., Chen, Y., Huang, S., Yao, D., … Li, Y. (2020). Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML. Biomarker Research, 8, 6.
Westin, J. R., Chu, F., Zhang, M., Fayad, L. E., Kwak, L. W., Fowler, N., … Neelapu, S. S. (2014). Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: A single group, open-label, phase 2 trial. The Lancet Oncology, 15(1), 69-77.
Williams, P., Basu, S., Garcia-Manero, G., Hourigan, C. S., Oetjen, K. A., Cortes, J. E., … Daver, N. G. (2019). 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, 125(9), 1470-1481.
Yang, H., Bueso-Ramos, C., DiNardo, C., Estecio, M. R., Davanlou, M., Geng, Q. R., … Garcia-Manero, G. (2014). Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 28(6), 1280-1288.
Younes, A., Santoro, A., Shipp, M., Zinzani, P. L., Timmerman, J. M., Ansell, S., … Engert, A. (2016). Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. The Lancet Oncology, 17(9), 1283-1294.
Zhou, Q., Munger, M. E., Highfill, S. L., Tolar, J., Weigel, B. J., Riddle, M., … Blazar, B. R. (2010). 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, 116(14), 2484-2493.
Zinzani, P. L., Ribrag, V., Moskowitz, C. H., Michot, J. M., Kuruvilla, J., Balakumaran, A., … Armand, P. (2017). Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood, 130(3), 267-270.

Keywords: B-lymphoblastic leukemia; T cell subsets; flow cytometry; immune checkpoint PD-1

0 (Apoptosis Regulatory Proteins)
0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (Immune Checkpoint Inhibitors)
0 (PDCD1 protein, human)
0 (PDCD1LG2 protein, human)
0 (Programmed Cell Death 1 Ligand 2 Protein)
0 (Programmed Cell Death 1 Receptor)

Date Created: 20200409 Date Completed: 20210823 Latest Revision: 20210823

20221213

10.1002/cyto.b.21879

32268011