Distinct immune signatures in chronic lymphocytic leukemia and Richter syndrome

Yucai Wang,Saad S Kenderian,Sameer A Parikh,Neil E Kay,Suzanne R Hayman,Wei Ding,Timothy G Call,Charla R Secreto,Karen L Rech,Jose F Leis,Rong He,Sutapa Sinha,Amber B Koehler,Haidong Dong,Eli Muchtar,Daniel L Van Dyke,Linda E Wellik,Susan L Slager

doi:10.1038/s41408-021-00477-5

Yucai Wang, Saad S Kenderian + Show 16 more

Open Access

https://doi.org/10.1038/s41408-021-00477-5

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Abstract

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th–75th], 0.107 [0.070–0.209] vs. 0.233 [0.111–0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world[1]
In this study, we demonstrated that CLL and Richter syndrome (RS) have distinct immune signatures in both the lymph nodes and peripheral blood
We found that expression of PD-L1 in histiocytes and PD1 in neoplastic B cells, as well as infiltration of FOXP3-positive T cells and CD163-positive macrophages were increased in RS compared to CLL lymph node samples

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the Western world[1]. The clinical presentation of CLL is heterogeneous, with a relatively indolent course in a subset of patients. The clinical outcome of CLL has improved significantly with the introduction of novel targeted agents such as the Bruton’s tyrosine kinase inhibitor ibrutinib[2,3,4,5,6] and the B-cell lymphoma 2 inhibitor venetoclax[7,8,9]. Richter syndrome (RS) refers to the transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS typically presents aggressively with prominent constitutional symptoms, significant lymphadenopathy, and rapid progression[10,11,12]. Patients with RS have a patients who develop RS while on ibrutinib or venetoclax have a median overall survival of ~4–12 months[13,14,15]

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