Diffuse large B-cell lymphoma (DLBCL) is infiltrated with activated CD8+ T-cells despite immune checkpoint signaling
Adam M. Greenbaum1, Jonathan R. Fromm2, Ajay K. Gopal1,3, A. McGarry Houghton1,4
1Clinical Research Division, Fred Hutchinson Cancer Research Center, 2Department of Laboratory Medicine, 3Division of Medical Oncology, 4Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
Correspondence to: A. McGarry Houghton, M.D.
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., D4-100, Seattle, WA 98109, USA
E-mail: houghton@fredhutch.org
Published online: May 13, 2022.
© The Korean Journal of Hematology. All rights reserved.

Abstract
Background: B-cell non-Hodgkin lymphomas (NHL) are hematologic malignancies that arise in the lymph node. Despite this, the malignant cells are not cleared by the immune cells present. The failure of anti-tumor immunity may be due to immune checkpoints such as the PD-1/PDL-1 axis, which can cause T-cell exhaustion. Unfortunately, unlike Hodgkin lymphoma, checkpoint blockade in NHL has shown limited efficacy.
Methods: We performed an extensive functional analysis of malignant and non-malignant lymph nodes using high dimensional flow cytometry. We compared follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and lymph nodes harboring reactive hyperplasia (RH).
Results: We identified an expansion of CD8+PD1+ T-cells in the lymphomas relative to RH. Moreover, we demonstrate that these cells represent a mixture of activated and exhausted T-cells in FL. In contrast, these cells are nearly universally activated and functional in DLBCL. This is despite expression of counter-regulatory molecules such as PD-1, TIM-3, and CTLA-4, and the presence of regulatory T-cells.
Conclusions: These data may explain the failure of single-agent immune checkpoint inhibitors in the treatment of DLBCL. Accordingly, functional differences of CD8+ T-cells between FL and DLBCL may inform future therapeutic targeting strategies.
Keywords: Lymphoma, immune microenvironment, Immune checkpoint inhibition


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