PD1 (CD279) and PD-L1 (CD274, B7H1) expression in primary central nervous system lymphomas (PCNSL)

Berghoff, Anna Sophie; Ricken, Gerda; Widhalm, Georg; Rajky, Orsolya; Hainfellner, Johannes A.; Birner, Peter; Raderer, Markus; Preusser, Matthias

doi:10.5414/np300698

Cited by 96 publications

(82 citation statements)

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“…To begin addressing this issue, we examined the effect of MERTK on the expression of the immune checkpoint blockades, Programmed death-ligand 1 (PD-L1) and 2 (PD-L2). PD-L1 and PD-L2 are often overexpressed in poorly immunogenic tumors, and allow cancers to evade host immune responses and promote cancer invasiveness (55)(56)(57)(58). In our study, when Mertk was constitutively activated in 293T cells by means of Fc-Mertk transfection, mRNA transcripts and surface expression of PD-L1 and PD-L2 were increased (Fig.…”

Section: Resultssupporting

confidence: 55%

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Nguyen

Tsou

Calarese

et al. 2014

Journal of Biological Chemistry

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Background: Overexpression of MERTK tyrosine kinase is observed in many human cancers. Results: MERTK has a potent gain-of-function capacity to stimulate efferocytosis in epithelial cells. Conclusion: When overexpressed, MERTK acts as a preeminent efferocytosis receptor that is targetable by soluble Ig-domain containing TAM receptors. Significance: Our findings provide new mechanistic insight into how MERTK may impinge on tumor progression by enhancing efferocytosis.

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Section: Resultssupporting

confidence: 55%

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Nguyen

Tsou

Calarese

et al. 2014

Journal of Biological Chemistry

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“…39,40 Moreover, the ABC subtype of DLBCL prominently expressed not only PD-L1, 36,41,42 but also PD-L2. This ABC DLBCL subtype is associated with an inferior survival prognosis compared to the GCB subtype.…”

Section: E1026530-8 Volume 4 Issue 8 Oncoimmunologymentioning

confidence: 99%

Several immune escape patterns in non-Hodgkin's lymphomas

et al. 2015

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Follicular Lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) must evolve some immune escape strategy to develop from lymphoid organs, but their immune evasion pathways remain poorly characterized. We investigated this issue by transcriptome data mining and immunohistochemistry (IHC) of FL and DLBCL lymphoma biopsies. A set of genes involved in cancer immune-evasion pathways (Immune Escape Gene Set, IEGS) was defined and the distribution of the expression levels of these genes was compared in FL, DLBCL and normal B cell transcriptomes downloaded from the GEO database. The whole IEGS was significantly upregulated in all the lymphoma samples but not in B cells or other control tissues, as shown by the overexpression of the PD-1, PD-L1, PD-L2 and LAG3 genes. Tissue microarray immunostainings for PD-1, PD-L1, PD-L2 and LAG3 proteins on additional biopsies from 27 FL and 27 DLBCL patients confirmed the expression of these proteins. The immune infiltrates were more abundant in FL than DLBCL samples, and the microenvironment of FL comprised higher rates of PD-1 C lymphocytes. Further, DLBCL tumor cells comprised a higher proportion of PD-1C, PD-L1 C , PD-L2C and LAG3 C lymphoma cells than the FL tumor cells, confirming that DLBCL mount immune escape strategies distinct from FL. In addition, some cases of DLBCL had tumor cells co-expressing both PD-1, PD-L1 and PD-L2. Among the DLBCLs, the activated B cell (ABC) subtype comprised more PD-L1C and PD-L2 C lymphoma cells than the GC subtype. Thus, we infer that FL and DLBCL evolved several pathways of immune escape.

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“…Another interesting path forward could be addressing the immunosuppressive microenvironment in PCNSL by PD1/PD-L1 axis inhibitors. 15 …”

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confidence: 99%

Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma

et al. 2015

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OBJECTIVE This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median followup of 81.2 months. METHODS Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)-based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9. RESULTS In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio [HR] . CONCLUSION Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma ABSTRACTObjective: This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months.Methods: Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)-based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9.Results: In the per-protocol population (n 5 320), WBRT nonsignificantly prolonged progressionfree survival (PFS) (median 18.2 vs 11.9 months, hazard ratio Conclusion:Although the statistical proof of noninferiority regarding OS was not given, our results suggest no worsening of OS without WBRT in primary therapy of PCNSL. Classification of evidence:This study provides Class II evidence that in PCNSL HDMTX-based chemotherapy followed by WBRT does not significantly increase survival compared to chemotherapy alone. The study lacked the precision to exclude an important survival benefit or harm from WBRT. Neurology ® 2015;84:1242-1248 GLOSSARY CHT 5 chemotherapy; CI 5 confidence interval; CR 5 complete response; G-PCNSL-SG 5 German PCNSL Study Group; HD-Ara-C 5 high-dose cytarabine; HDMTX 5 high-dose methotrexate; HR 5 hazard ratio; ITT 5 intent-to-treat; KPS 5 Karnofsky Performance Score; OS 5 overall survival; PCNSL 5 primary CNS lymphoma; PFS 5 progression-free survival; PP 5 per protocol; PR 5 partial remission; WBRT 5 whole-brain radiotherapy.Standards of care have not been well-defined for primary CNS lymphoma (PCNSL). Highdose methotrexate (HDMTX) is the only undisputed standard of care, whereas the addition of whole-brain radiotherapy (WBRT) has been increasingly questioned because of the high frequency of late neurotoxicity ...

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PD1 (CD279) and PD-L1 (CD274, B7H1) expression in primary central nervous system lymphomas (PCNSL)

Abstract: PD1 and PDL1 are immunohistochemically detectable in PCNSL and may be involved in creating an immunosuppressive microenvironment. Specific immune checkpoint inhibitors may be considered for experimental therapy approaches in this disease.

Cited by 96 publications

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Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Overexpression of MERTK Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity

Several immune escape patterns in non-Hodgkin's lymphomas

Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma

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