Lack of Viral Load Within Chronic Lymphoproliferative Disorder of Natural Killer Cells: What Is Outside the Leukemic Clone?

Edoardo Giussani,Gregorio Barilà,Stefania Bortoluzzi,Giulia Calabretto,Vanessa Rebecca Gasparini,Renato Zambello,Antonella Teramo,Andrea Binatti,Alessandro Coppe,Cristina Vicenzetto,Monica Facco,Gianpietro Semenzato

doi:10.3389/fonc.2020.613570

Edoardo Giussani, Gregorio Barilà + Show 10 more

Open Access

https://doi.org/10.3389/fonc.2020.613570

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Abstract

Large granular lymphocyte leukemias (LGLL) are sustained by proliferating cytotoxic T cells or NK cells, as happens in Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK), whose etiology is only partly understood. Different hypotheses have been proposed on the original events triggering NK cell hyperactivation and transformation, including a role of viral agents. In this perspective, we revise the lines of evidence that suggested a pathogenetic role in LGLL of the exposure to retroviruses and that identified Epstein Barr Virus (EBV) in other NK cell leukemias and lymphomas and focus on the contrasting data about the importance of viral agents in CLPD-NK. EBV was detected in aggressive NK leukemias but not in the indolent CLPD-NK, where seroreactivity against HTLV-1 retrovirus envelope BA21 protein antigens has been reported in patients, although lacking clear evidence of HTLV infection. We next present original results of whole exome sequencing data analysis that failed to identify viral sequences in CLPD-NK. We recently demonstrated that proliferating NK cells of patients harbor several somatic lesions likely contributing to sustain NK cell proliferation. Thus, we explore whether “neoantigens” similar to the BA21 antigen could be generated by aberrancies present in the leukemic clone. In light of the literature and new data, we evaluated the intriguing hypothesis that NK cell activation can be caused by retroviral agents located outside the hematopoietic compartment and on the possible mechanisms involved with the prospects of immunotherapy-based approaches to limit the growth of NK cells in CLPD-NK disease.

Highlights

Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK) belongs to the group of large granular lymphocyte leukemias (LGLL), sustained by cytotoxic T cells (T-LGL) or NK cells
Seroreactivity against HTLV-1 envelope protein antigens has been reported in CLPD-NK, patients were not demonstrated to be infected with a prototypical HTLV retrovirus [9]
We considered that a peculiar feature reported for the majority of CLPD-NK cases is represented by seroreactivity against BA21, a peptide derived from HTLV-I envelope protein p21 [9]

Summary

INTRODUCTION

Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK) belongs to the group of large granular lymphocyte leukemias (LGLL), sustained by cytotoxic T cells (T-LGL) or NK cells. Several studies showed that Whole Exome Sequencing (WES) data of cancer cells can be useful to identify pathogens, viruses, in cancer clones and to define possible sites of integration in the host genome or their presence in episomal forms [10, 11] In both ANKL and NKTCL, a larger EBV load in tumor clones than control cells of the same patient has been detected by WES [11]. KIR3DS1 recognizes peptides modulated by HLA-Bw4 alleles playing a crucial role in NK cell education [34], and the highest cytotoxic potential was detected when Bw4I80 is lacking In this regard, we previously showed that HLA-I/KIR mismatch is often present in NK cell proliferation in CLPD-NK [2, 35].

CONCLUSIONS

Findings

ETHICS STATEMENT