Research Paper Volume 13, Issue 1 pp 181—193

The adhesion molecule ICAM-1 in diffuse large B-cell lymphoma post-rituximab era: relationship with prognostic importance and rituximab resistance

Yizhen Liu1, *, , Juan J. Gu2,3, *, , Ling Yang4, *, , Ping-Chiao Tsai3, , Ye Guo5, , Kai Xue1, , Zuguang Xia1, , Xiaojian Liu1, , Fangfang Lv1, , Junning Cao1, , Xiaonan Hong1, , Cory Mavis2,3, , Francisco J. Hernandez-Ilizaliturri2,3, , Qunling Zhang1, ,

  • 1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
  • 2 Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14203, USA
  • 3 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14203, USA
  • 4 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
  • 5 Department of Medical Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
* Equal contribution

Received: February 26, 2020       Accepted: September 24, 2020       Published: December 3, 2020      

https://doi.org/10.18632/aging.202180
How to Cite

Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (P=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.

Abbreviations

ICAM-1: Intercellular adhesion molecule-1; DLBCL: diffuse large B-cell lymphoma; GCB: germinal center B-cell; IPI: International Prognostic Index; RSCL: rituximab sensitive cell line; RRCL: rituximab resistant cell line; PFS: progression-free survival; ORR: overall response rate; OS: overall survival; ADCC: antibody-dependent cellular cytotoxicity; CMC: complement-mediated cytotoxicity.