Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of immunohistochemical studies

Abstract

Immune checkpoint blockade therapeutics, notably antibodies targeting the programmed death 1 (PD-1) receptor and its PD-L1 and PD-L2 ligands, are currently revolutionizing the treatment of cancer. For a sizeable fraction of patients with melanoma, lung, kidney and several other solid cancers, monoclonal antibodies that neutralize the interactions of the PD-1/PD-L1 complex allow the reconstitution of long-lasting antitumor immunity. In hematological malignancies this novel therapeutic strategy is far less documented, although promising clinical responses have been seen in refractory and relapsed Hodgkin lymphoma patients. This review describes our current knowledge of PD-1 and PD-L1 expression, as reported by immunohistochemical staining in both non-Hodgkin lymphoma cells and their surrounding immune cells. Here, we discuss the multiple intrinsic and extrinsic mechanisms by which both T and B cell lymphomas up-regulate the PD-1/PD-L1 axis, and review current knowledge about the prognostic significance of its immunohistochemical detection. This body of literature establishes the cell surface expression of PD-1/PD-L1 as a critical determinant for the identification of non-Hodgkin lymphoma patients eligible for immune checkpoint blockade therapies.

Keywords: PD-1/PD-L1 expression; non-Hodgkin lymphoma; prognostic value.

Figure 1. General mechanisms that lead to PD-L1 overexpression in lymphoma

Genetic alterations to the PD-L1 and PD-L2 locus of chromosome 9p24.1 (gains, amplifications or fusions) directly induce the activation of the PD-L1 promoter and thus PD-L1 overexpression [35, 43]. PD-L1 expression can also be induced by activation of the JAK/STAT pathway via inflammatory cytokines such as IL10 [13, 39]. This is through activation of JAK2 via either its molecular alteration, the inhibition of SOCS-1 [36] or by microRNA miR-135a [37]. EBV infection directly activates the PD-L1 promoter via the AP-1/cJUN/JUN-B pathway and indirectly activates it via the activation of JAK3-STAT5 by inflammatory cytokines (IFN) [13, 43]. Other indirect processes that may result in molecular anomalies that induce the activation of the JAK/STAT pathway typically include the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation in NPM-ALK-positive anaplastic large cell lymphoma (ALCL) [40, 41] or the MYD88 L265P mutation in diffuse large B cell lymphoma [42].

Figure 2. PD-1/PD-L1 protein expression in non Hodgkin lymphoma

A. PD-1 staining positive in DLBCL tumor cells (x400); the magnified insert showed PD-1⁺ (brown) / PAX5⁺ (red) tumor cells (x400). B. PD-L1 staining positive in DLBCL tumor cells (x400); the magnified insert showed PD-L1⁺ (brown) / PAX5⁺ (red) tumor cells (x400). C. PD-1 staining showing PD-1⁺ T_FH cells with an intrafollicular pattern in FL samples (x100; magnified insert x200). D. PD-L1 staining showing PD-L1⁺ macrophages in the FL ME (x100). E. PD-1 staining showing PD-1⁺ cells in CLL proliferative centers (x100); the magnified insert showed PD-1⁺ (brown) / PAX5⁺ (red) neoplastic B cells in proliferative center (x200). F. PD-1 staining in AITL samples showing PD-1⁺ tumor cells (x200). D. PD-L1 staining showing PD-L1 ⁺ macrophages in the FL ME (x100; magnified insert x100). F. PD-1 staining in AITL samples showing PD-1 ⁺ tumor cells (x200; magnified insert x400).

Figure 3. PD-1/PD-L1 expression and their prognostic value in diffuse large B cell lymphoma

Figure 4. PD-1/PD-L1 expression and their prognostic value in follicular lymphoma