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Comprehensive immunohistochemical analysis of immune checkpoint molecules in adult T cell leukemia/lymphoma

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Abstract

Acute or lymphomatous type adult T cell leukemia/lymphoma (ATLL) is an aggressive hematopoietic malignancy with poor prognosis. We previously reported that programmed cell death ligand 1 (PD-L1) expression could predict ATLL outcomes. However, the roles of other immune checkpoint molecules remain largely unknown in ATLL. Our aim in this study was to explore the clinicopathological impacts of immune checkpoint molecules in ATLL. Immunohistochemistry was performed in 69 ATLL patients with antibodies against the following: PD-L1, programmed cell death ligand 2 (PD-L2), OX40, OX40 ligand (OX40L), CD137, CD137 ligand (CD137L), Galectin-9, T cell immunoglobulin mucin-3 (Tim-3), cytotoxic T lymphocyte associated protein-4 (CTLA-4), lymphocyte activating-3 (LAG-3), CD80, CD86, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), GITR ligand (GITRL), and programmed death-1 (PD-1). Immune checkpoint molecules were variably expressed on neoplastic and/or microenvironmental cells. Expression of PD-1, OX40L, Galectin-9, and PD-L1 was nearly mutually exclusive on neoplastic cells, suggesting that immune checkpoint pathways differ in patients. Microenvironmental expression of PD-L1, OX40L, and Tim-3 was significantly associated with better overall survival (log-rank test; P =0.0004, 0.0394, and 0.0279, respectively). Univariate and multivariate analyses with clinical prognostic factors identified microenvironmental expression of PD-L1 and OX40L, and age (> 70 years) as significant prognostic factors. This is the first comprehensive analysis of ATLL immune checkpoint molecules. Our results may provide information on new therapeutic strategies in ATLL.

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Acknowledgments

The authors thank Mayumi Miura, Kanoko Miyazaki, and Chie Kuroki for their technical assistance. The language and format of this manuscript have been edited by Editage (https://www.editage.com).

Funding

This work was supported in part by Grants-in-Aid from the Japan Agency for Medical Research and Development (grant number 15ck0106015h0002) (MS) and the Japan Society for the Promotion of Science (KAKENHI) (grant JP26460446) (KO), (grant number JP17K17894) (MT).

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Correspondence to Hiroaki Miyoshi.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (include name of committee + reference number) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kaplan–Meier plots depicting the survival differences between patients positive and negative for immune checkpoint molecule expression on microenvironmental cells. mi, microenvironmental; OS, overall survival; GITR, glucocorticoid-Induced tumor necrosis receptor-related protein; PD-1, programmed death-1; CTLA-4, cytotoxic T lymphocyte-associated antigen; PD-L2, programmed cell death ligand-2; LAG-3; lymphocyte-activating 3.

Kaplan–Meier plots depicting the survival differences between patients positive and negative for immune checkpoint molecule expression on neoplastic cells. n, neoplastic; OS, overall survival; PD-L1, programmed cell death ligand-1; PD-1, programmed death-1.

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Takeuchi, M., Miyoshi, H., Nakashima, K. et al. Comprehensive immunohistochemical analysis of immune checkpoint molecules in adult T cell leukemia/lymphoma. Ann Hematol 99, 1093–1098 (2020). https://doi.org/10.1007/s00277-020-03967-x

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