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

Dysfunctional anti-tumor immunity is 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 the disease development is still undetermined. In the current study, we sought to explore features and pathogenetic significance of exhausted T cells using a mouse model with de novo mature B cell neoplasms, which is likely to show immune escape similar to human patients. We found that PD-1+ Tim-3- and PD-1+ Tim-3+ T cells with positive CD8 were significantly increased in sick mice. Furthermore, PD-1+ Tim-3+ T cells had great direct cytotoxic ability with short lives, exhibiting transcriptional similarity to terminally exhausted T cells. On the other hand, PD-1+ Tim-3- T cells not only indicated immunological responsiveness but also retained stem-like transcriptional features, suggesting that PD-1+ Tim-3- T cells might play a role to maintain anti-tumor immunity for a long time. In PD-1+ Tim-3- and PD-1+ Tim-3+ T cells, transcription factors Tox, Nr4a2, which were reported to progress T cell exhaustion, were upregulated in vivo. Importantly, these transcription factors were downregulated by IMiDs in our in vitro T cell exhaustion analyses. Preventing excessive T cell exhaustion possibly maintains effective anti-tumor immunity to achieve the cure of mature B cell neoplasms.