The pathogenetic significance of exhausted T cells in a mouse model of mature B cell neoplasms

Abstract

Dysfunctional anti-tumor immunity has been implicated in the pathogenesis of mature B cell neoplasms, such as multiple myeloma and B cell lymphoma; however, the impact of exhausted T cells on disease development remains unclear. Therefore, the present study investigated the features and pathogenetic significance of exhausted T cells using a mouse model of de novo mature B cell neoplasms, which is likely to show immune escape similar to human patients. The results revealed a significant increase in PD-1⁺ Tim-3^- and PD-1⁺ Tim-3⁺ T cells in sick mice. Furthermore, PD-1⁺ Tim-3⁺ T cells exhibited direct cytotoxicity with a short lifespan, showing transcriptional similarities to terminally exhausted T cells. On the other hand, PD-1⁺ Tim-3^- T cells not only exhibited immunological responsiveness but also retained stem-like transcriptional features, suggesting that they play a role in the long-term maintenance of anti-tumor immunity. In PD-1⁺ Tim-3^- and PD-1⁺ Tim-3⁺ T cells, the transcription factors Tox and Nr4a2, which reportedly contribute to the progression of T cell exhaustion, were up-regulated in vivo. These transcription factors were down-regulated by IMiDs in our in vitro T cell exhaustion analyses. The prevention of excessive T cell exhaustion may maintain effective anti-tumor immunity to cure mature B cell neoplasms.

Keywords: Exhausted T cell; Mature B cell neoplasm; Mouse model; Multiple myeloma. IMiDs.