Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Abstract

Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.

Keywords: Richter syndrome; chronic lymphocytic leukemia; immune dysfunction; immunotherapy.

Figure 1

Immune microenvironment interactions in RS. RS tumor cells can act as PD-1⁺ Bregs, promoting T cell exhaustion and immunosuppressive T regulatory lymphocytes expansion via IL-10 secretion or through the interaction with PD-L1 expressed on the surface of DCs and tumor-infiltrating histocytes. Other immune-suppression mechanisms include T cell function inhibition consequent to activation of the immune checkpoints LAG3, found on the cell membrane of T lymphocytes, and TIGIT, on the surface of T and NK cells. Lastly, CD226 hyperexpression and interaction with CD155, expressed on APCs, may act as a positive activator of BCR signaling in RS cells. In a physiological setting, CD 226 acts as a positive activator of T cell response when expressed on the surface of these cells, competing against TIGIT for the binding with CD155. Abbreviations: Breg, B regulatory cell; DC, dendritic cell; Treg, T regulatory cell; APC, antigen presenting cell; RS, Richter syndrome. Image created with Biorender.com (accessed on 7 December 2022).

Figure 2

Druggable targets of CIT and immunotherapy in RS. Different CIT and immunotherapy approaches may be used for RS treatment, including chemotherapy in combination with anti-CD20 naked mAbs, PD-1/PD-L1 checkpoint inhibitors in combination with small molecule inhibitors or other mAbs, CD19 × CD3 or CD20 × CD3 bsAbs, anti-CD30, anti-ROR1 or anti-CD37 ADCs, and anti-CD19 CAR-T cells. Abbreviations: APC, antigen presenting cell; CAR, chimeric antigen receptor; ROR1, receptor tyrosine kinase-like orphan receptor 1; ATACs, amanitin-based antibody-drug conjugates; RS, Richter syndrome. Image created with Biorender.com (accessed on 7 December 2022).