PD-L1 Expression Is Characteristic of a Subset of Aggressive B-cell Lymphomas and Virus-Associated Malignancies

Abstract

Purpose Programmed death ligand 1 (PD-L1) is an immunomodulatory molecule expressed by antigen-presenting cells and select tumors that engage receptors on T cells to inhibit T-cell immunity. Immunotherapies targeting the PD-1/PD-L1 pathway have shown durable anti-tumor effects in a subset of patients with solid tumors. PD-L1 can be expressed by Reed-Sternberg cells comprising classical Hodgkin lymphoma (CHLs) and by malignant B cells comprising EBV-positive post-transplant lymphoproliferative disorders (PTLDs). We sought to determine whether the expression of PD-L1 represents a general strategy of immune evasion among aggressive B-cell lymphomas and virus- and immunodeficiency-associated tumors. Experimental Design Using novel antibodies and formalin-fixed, paraffin-embedded (FFPE) tissue biopsies, we examined 237 primary tumors for expression of PD-L1 protein. Results Robust PD-L1 protein expression was found in the majority of nodular sclerosis CHL, mixed cellularity CHL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich B-cell lymphoma, EBV-positive and -negative PTLD, and EBV-associated diffuse large B-cell lymphoma (DLBCL), plasmablastic lymphoma, extranodal NK/T cell lymphoma, nasopharyngeal carcinoma, and HHV8-associated primary effusion lymphoma. Within these tumors, PD-L1 was highly expressed by malignant cells and tumor-infiltrating macrophages. In contrast, neither the malignant nor the non-malignant cells comprising nodular lymphocyte-predominant Hodgkin lymphoma, DLBCL-not otherwise specified, Burkitt lymphoma, and HHV8-associated Kaposi sarcoma expressed detectable PD-L1. Conclusion Certain aggressive B-cell lymphomas and virus- and immunodeficiency-associated malignancies associated with an ineffective T-cell immune response express PD-L1 on tumor cells and infiltrating macrophages. These results identify a group of neoplasms that should be considered for PD-1/PD-L1-directed therapies, and validate a method to detect PD-L1 in FFPE tissue biopsies.

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

“…The in vitro findings suggest that EBV infection may happen first in the pathogenesis of NPC and MSI can be induced by EBV. In addition, our results confirm findings of other studies [14][15][16][17] that positive PD-L1 expression is frequent in NPCs, but is not associated with clinicopathologic parameters. Although it was previously reported as an independent predictor of survival [16], in our cohort from the Philippines, positive PD-L1 expression was not associated with OS.…”

“…In addition, it is important to note that the PD-L1 monoclonal antibody used in our study is different from antibodies used in previous reports. These studies have used a number of monoclonal antibodies for immunohistochemistry and immunofluorescence and a variety of different scoring schemes/criteria to define positive PD-L1 expression [14][15][16][17]. Therefore, a more detailed comparison of our results with those reported in literature is difficult.…”

“…PD-L1 expression was described in other EBV-associated malignancies [11][12][13] and several studies have reported positive PD-L1 expression in 25-89% of NPCs [14][15][16][17]. In contrast to EBV-associated gastric adenocarcinomas in which expression of PD-L1 protein may result from PD-L1 gene amplification [18], NPCs do not have PD-L1 gene copy number change [19].…”

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

“…6,34 During antitumor immune responses in vivo, various immune and tumor cells produce cytokines that upregulate PD-L1 (CD274) extrinsically in a paracrine and/or autocrine manner. 6,35 In contrast, an intrinsic mechanism refers to constitutive PD-L1 expression by oncogenic signaling, such as NPM-ALK translocation, PI3K/Akt activation, or chronic viral infection, 26,34,36 suggesting that intrinsic genetic alterations in tumor cells might account for regulation of the PD-1/PD-L pathway. Moreover, several driver mutations have emerged as therapeutic targets for patients with pulmonary adenocarcinoma.…”

“…[24][25][26] Thus, to determine the appropriate antibody to evaluate PD-L1 expression, we tested staining patterns of several commercially available antibodies against PD-L1 in human placenta and Epstein-Barr virus-positive nasopharyngeal carcinoma. A rabbit anti-PD-L1 (E1L3N) XP monoclonal antibody (Cell Signaling Technology, Danvers, MA, USA) showed the appropriate specificity and sensitivity with a clear membranous and/or cytoplasmic staining pattern and used in this study (Supplementary Figure S1).…”