Japanese researchers discover new mechanisms of action by extracellular vesicles in lymphoma

Japanese collaborative research teams have discovered new mechanisms of action by extracellular vesicles (EV) for the development and malignant progression of lymphomas.

Professor Ai Kotani and Kai Kudo, a graduate student, at the Tokai University has been investigating the roles of EV in the development of Epstein-Barr virus (EBV) -positive B-cell malignant lymphomas, but the mechanism of its action has not been fully clarified. Meanwhile, Professor Makoto Murakami and Yoshimi Miki researcher at the University of Tokyo has been clarifying a number of vital phenomena to which "secretory phospholipase A2 (sPLA₂)" is involved. sPLA₂ is a phospholipid-degrading enzyme existing in the extracellular environment; however, the source of the phospholipids that sPLA₂ uses as a substrate outside cells has been unknown.

In this study, the research groups demonstrated that sPLA₂ secreted from tumor-associated macrophage (TAM) in malignant lymphoma tissue degrades phospholipid of EV derived from tumor cells. They also found that this degradation dramatically improves EV function, such as "ease of cellular uptake" and "immunosuppressive effect," and induction of various vital phenomena. Moreover, they discovered that lysophospholipids, degraded products of EV phospholipids, transmit signals to cells, namely, novel mechanisms of action that have not been known in EV biology. Using model mice that reproduce the development of lymphomas in humans, the research groups demonstrated that EV-degradation by sPLA₂ is essential for tumorigenesis. Analysis of samples from patients with lymphoma also showed that sPLA₂ is involved in tumorigenesis and malignant progression.

On the other hand, the study demonstrated that not only lymphoma-derived EVs but also EVs derived from other cancer cells are degraded by sPLA₂ and revealed that the sPLA₂-EV axis is a common phenomenon in tumorigenesis. Therefore, it is expected that this sPLA₂-EV axis will become a new drug target for cancer treatment as a new "immune checkpoint." In addition, based on sPLA₂'s EV function enhancement demonstrated in this study, they are currently testing hypotheses that sPLA₂ may enhance inherent abilities of various types of EV, such as "EV with tissue protecting and anti-inflammatory effects" previously reported by the Kotani's group, and further development for therapeutic applications in the future is expected.

This research was conducted under the JST Strategic Basic Research Programs and the AMED Cancer Research Program in collaboration with following members. Professor Kiyoshi Ando, Professor Naoya Nakamura, and Instructor Joaquim Carreras, Tokai University School of Medicine, Associate Professor Asuka Inoue, Tohoku University, Associate Professor Kei Yamamoto, Tokushima University, Researcher Hiroshi Higuchi, Massachusetts General Hospital and Harvard Medical School, Professor Shinya Morita, Shiga University of Medical Science Hospital, and Professor Junken Aoki, The University of Tokyo.