PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

Abstract

Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1-and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0-94.6) than intratumoral macrophages (27.5%; 95% CI: 0-81.1, p = 0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2positive peritumoral macrophages (p = 0.0429), with very low coefficient correlation (ρ = 0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p = 0.0008; better MSKCC score, p = 0.0103; peritumoral macrophages: low proportion of LDH elevation, p = 0.0064) and longer OS (for intratumoral macrophages: high PD-L1 = 60 months, 95% CI = 30-132.6; low PD-L1 = 24 months, 95% CI = 11-48; p = 0.032; for peritumoral macrophages: high PD-L1 = 60 months, 95% CI = 30.7-NR; low PD-L1 = 14 months, 95% CI = 3-26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR = 0.30, 95% CI = 0.12-0.77, p = 0.0129).

Sialic acid-binding immunoglobulin-like lectin-15 expression on peritumoral macrophages is a favorable prognostic factor for primary central nervous system lymphoma patients

“…Various studies have investigated the PD-L1 expression in the PCNSL microenvironment. According to past reports, the expression of PD-L1 is more frequently detected on tumor infiltrating cells, including macrophages than tumor cells 10 , 13 , 15 – 17 . Our results show similar trends.…”

“…Regarding the association between PD-L1 and survival in patients with PCNSL, the past literature showed that the PD-L1 expression in tumor cells was correlated with overall survival and that the median survival time was not reached among patients with PD-L1-positive tumor cells and 31.7 months among those with PD-L1-negative tumor cells, although the PD-L1 expression in tumor stromal cells was not correlated with overall survival 10 . On the other hand, Furuse et al analyzed the expression of PD-L1 and PD-L2 in both tumor and peritumoral tissues and revealed that PD-L1-positivity of intratumoral and peritumoral macrophages predicted a favorable outcome 13 . Our results showed that tumor cell PD-L1 positivity was associated with longer overall survival in comparison to PD-L1 negativity; however, this factor was excluded by a multivariate Cox regression analysis.…”

“…Based on these results Siglec-15 become a therapeutic target in DLBCL. Various reports have discussed the association of the immune checkpoint molecule expression on tumor cells and/or macrophages and overall survival; however, no reports have mentioned the correlation between the Siglec-15 expression on macrophages and overall survival in patients with PCNSL 9 – 13 . A study of primary testicular lymphoma found that patients with the high expression of PD-L1 on macrophages showed favorable survival 20 .…”

“…Another meta-analysis evaluated the prognostic value of the PD-L1 expression in tumor infiltrating immune cells and suggested that PD-L1 positivity in tumor infiltrating immune cells indicated a better prognosis in breast cancer patients 12 . With regard to lymphoma, recent studies have shown that the PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome 13 . However, there are no reports analyzing the association between the expression of Siglec-15—which seems to be mutually exclusive against PD-L1—on tumor cells and macrophages with the survival in patients with PCNSL.…”

Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies

“…Additionally, PD-L2 is also expressed on tumor cells and involved in antitumor immune suppression (Latchman et al, 2001;Taube et al, 2014;Yearley et al, 2017;Larsen et al, 2019;Liao et al, 2019;Tanegashima et al, 2019;Nakayama et al, 2020). Moreover, PD-L2 not only possesses higher affinity for PD-1 than PD-L1 does but also may be highly coexpressed with PD-L1 in tumor cells and tissues (Youngnak et al, 2003;Cheng et al, 2013;Morales-Betanzos et al, 2017;Tang and Kim, 2019;Furuse et al, 2020;Wolkow et al, 2020). It is worth mentioning that proteolytic degradation or alternative splice variants also produce soluble PD-L2, which may be a complementary biomarker (He et al, 2004;Dai et al, 2014;Fukasawa et al, 2017;Costantini et al, 2018;Buderath et al, 2019;.…”