Seishi Ogawa wins Takeda Medical Prize (21 September 2017)

On 21 September, Takeda Science Foundation announced they will be awarding the 2017 Takeda Medical Prize (Takeda Igaku Sho) to two researchers, including Professor Seishi Ogawa of the Kyoto University Graduate School of Medicine.

Now in its 61st year, the Prize annually honors scholars and researchers who have made significant contributions to the study or practice of medicine through outstanding achievements in the field.

Professor Ogawa was awarded the Prize for his "Comprehensive analysis of the molecular basis of adult T-cell leukemia/lymphoma (ATL) and elucidation of the immune evasion mechanism of cancers".

ATL is a highly malignant T-cell neoplasm caused by the human T-cell leukemia virus type-1 (HTLV-1), which is endemic in Japan and several other regions.

HTLV-1 infection alone does not cause ATL. It had been suggested that accumulation of genetic mutations in T cells after the first infection in early childhood is required for the disease's onset in adulthood. Little had been known, however, as to the specific targets of such mutations.

Through integrated genomic analysis of over ATL 300 cases, with whole-genome sequencing performed on some patients, Professor Ogawa and colleagues systematically identified somatic mutations in at least 50 sets of genes. These genes were associated with: T-cell receptor/NFκB signaling pathways (such as PLCγ1, PKCβ, CARD11, RHOA, IRF1, and CD28/CTLA4), transcription factors involved in T-cell differentiation (such as IKZF2, GATA3, and TBL1XR1), G-protein-coupled receptors (CCR4, CCR7, and GPR183), epigenetic control factors, and cell-cycle and DNA-repair pathways.

These findings presented, for the very first time, a comprehensive picture of the genetic alterations associated with ATL, making them the most significant milestone in the understanding of ATL pathology since the discovery of HTLV-1. They have substantially advanced the understanding of the disease's molecular pathogenesis, potentially paving the way for the development of drugs targeting mutated proteins such as PLCγ1 and PKCβ.

Professor Ogawa’s other outstanding achievement, also a result of the comprehensive genome analysis of ATL, is the discovery of structural variations to the PD-L1 gene, and their role in aiding immune evasion by tumor cells.

Specifically, he found that structural variations disrupting gene regions, such as the 3’ untranslated region (UTR) of the PD-L1 gene, were present in a quarter of ATL cases investigated, and that these variations led to over-expression of the PD-L1 protein, contributing to tumor immune evasion. He concluded that this PD-L1-mediated immune escape was a key step in the development of ATL. Additionally, he revealed that this mechanism is widely observed among malignant lymphomas as well as solid tumors, and that immune checkpoint inhibitors can suppress tumor growth in these diseases.

The revelation of the PD-L1 expression mechanism involving 3'-UTR has shed new light on tumor immune evasion. It also suggests that structural variations converging on PD-L1 3’-UTR and other regions could serve as a genetic marker to identify patients likely to benefit from immune checkpoint blockade.

Thus, Professor Ogawa's discoveries have significantly advanced the understanding of ATL development and tumor immune escape, making it deserving of the 2017 Takeda Prize.

The award ceremony was held 13 November in Tokyo.