Genetic mechanism involving PD ligands to promote immune evasion in multiple cancers

Dear All,

Cell Signal Unit (Yamamoto Unit) would like to inform you of a seminar by Dr. Keisuke Kataoka from National Cancer Center Research Institute.

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Date: Wednesday, February 28, 2018

Time: 14:00-15:00

Venue: C016, Level C, Lab 1

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Speaker:

Dr. Keisuke Kataoka, Chief of Division of Molecular Oncology, National Cancer Center Research Institute

Title:
Genetic mechanism involving PD ligands to promote immune evasion in multiple cancers

Abstract:
Successful treatment of advanced cancer patients using anti-PD-1/PD-L1 antibodies has highlighted a critical role of immune checkpoint-mediated immune evasion in human cancers. However, the genetic basis for the immune escape remains elusive. Here we demonstrate a novel genetic mechanism to mediate immune evasion caused by structural variations (SVs) disrupting the 3′ part of the PD-L1 and/or PD-L2 genes in a variety of malignancies, especially in lymphomas. Initially, using whole-genome sequencing analysis of adult T-cell leukemia/lymphoma (ATL), followed by pan-cancer sequencing analysis of >10,000 cases in 33 cancer types, we identified PD-L1 SVs in ATL (27%), diffuse large B-cell lymphoma (8%) and several kinds of solid cancers, such as gastric (2%) and cervical (1%) cancers. All SVs affected PD-L1 3′-UTR and were associated with a marked increase of PD-L1 expression, irrespective of PD-L1 copy number. CRISPR/Cas9-mediated disruption of the 3′-UTR in tumor cell lines induced PD-L1 overexpression and promoted tumor progression and immune escape in vivo, which was effectively cancelled by Pd-1/Pd-l1 blockade therapy. Prompted by these findings, we investigated SVs involving PD-L1 and/or PD-L2 in patients with various malignancies using targeted capture sequencing, which showed a high frequency of these SVs in a subset of lymphomas, such as primary mediastinal B-cell lymphoma or Epstein-Barr virus-associated lymphomas. These findings not only reveal a novel regulatory machinery of PD-L1/PD-L2 expression, but also provide a possibility that PD-L1/PD-L2 3′-UTR disruption could serve as a biomarker to identify patients who are likely to benefit from PD-1/PD-L1 blockade in human malignancies.

Host:
Prof. Tadashi Yamamoto

We hope to see many of you at the seminar.

Best regards,

Yuki Nakagawa

Research Unit Administrator

Cell Signal Unit