PD-1 Expression in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Large B-cell Richter Transformation (DLBCL-RT)

Abstract

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ∼2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT. We evaluated PD-1 and PD-L1 expression by immunohistochemistry in 39 CLL/SLL, 15 DLBCL-RT, and 26 other DLBCL. In CLL/SLL, neoplastic B-cell PD-1 expression was weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers (PCs) and accentuated PCs of all sizes. Neoplastic B-cell PD-1 expression was highly prevalent and demonstrated increased intensity in DLBCL-RT, but in contrast was only rarely seen in other DLBCL (12/15 vs. 1/26; P<0.0001). An excellent correlation (90% concordance) was observed between neoplastic B-cell PD-1 immunohistochemistry positivity and molecularly defined CLL/SLL clonal relatedness in DLBCL-RT. PD-L1 expression was observed on the neoplastic B cells in rare DLBCL-RT and other DLBCL cases (1/15 vs. 1/26; P>0.05) as well as background histiocytes and dendritic cells. Overall survival of DLBCL-RT was significantly inferior to that of the other DLBCL (median, 16.9 vs. 106.1 mo; P=0.002). Our findings suggest a biological continuum from prolymphocytes/paraimmunoblasts in CLL/SLL PCs to the neoplastic B-cells in DLBCL-RT. The characteristic PD-1 expression in DLBCL-RT makes it a potential surrogate marker for determining clonal relatedness to CLL/SLL, which may have important prognostic and therapeutic implications.

Clinicopathological evaluation of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in post‐transplant lymphoproliferative disorders: association with Epstein–Barr virus, PD‐L1 copy number alterations, and outcome

“…Additionally, we identified a subgroup of polymorphic cases with a low density of PD1‐positive TILs who, even when treated with conventional therapy, had a worse prognosis. These PD1‐positive TILs may represent primarily activated lymphoid cells that are immunologically functional, or may correspond to residual follicular helper T cells of germinal centres . The limited number of patients in this subgroup prevents us from drawing any conclusions.…”

Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

“…Richter transformation represents transformation of CLL to DLBCL (RT-DLBCL) and is associated with a poor prognosis when the transformation is clonally associated with the underlying CLL (80% of cases) [ 103 ]. Interestingly, unlike CLL, tumor cells in RT-DLBCL express high levels of PD-1 [ 104 , 105 ], which is uncommon in de novo DLBCL. Genetic events associated with this phenomenon have not been elucidated.…”

“…This observation suggests that PD-1 expression in CLL tumor cells may promote further independence from adaptive immunity and stimulate tumor growth and clonal evolution. PD-1 expression may well serve as a marker of clonal relatedness to CLL and differentiate RT-DLBCL from de novo DLBCL [ 104 ]. These observations suggest that the PD-1 blockade may have therapeutic potential in RT-CLL.…”

<p>Immunochemotherapy for Richter syndrome: current insights</p>

“…Both these features may be due to the 24-fold increase in the transformation risk of this subset. In addition, DLBCL-RS cases, especially those clonally related to the underlying CLL, were shown to express the programmed death-1 transmembrane protein (PD-1, CD279) 35,36. Through the interaction with its ligands, PD-L1 and PD-L2 form a key immune checkpoint by downregulating T-cell activation and autoimmunity, thereby promoting self-tolerance, and by enabling malignant traits of CLL cells to be acquired, thus potentially leading to the development of RS 35–37…”