Venetoclax imparts distinct cell death sensitivity and adaptivity patterns in T cells

BH3 mimetics are increasingly used as anti-cancer therapeutics either alone or in conjunction with other chemotherapies. However, mounting evidence has also demonstrated that BH3 mimetics modulate varied amounts of apoptotic signaling in healthy immune populations. In order to maximize their clinical potential, it will be essential to understand how BH3 mimetics affect discrete immune populations and to determine how BH3 mimetic pressure causes immune system adaptation. Here we focus on the BCL-2 specific inhibitor venetoclax (ABT-199) and its effects following short-term and long-term BCL-2 blockade on T cell subsets. Seven day short-term ex vivo and in vivo BCL-2 inhibition led to divergent cell death sensitivity patterns in CD8(+) T cells, CD4(+) T cells, and Tregs resulting in shifting of global T cell populations towards a more memory T cell state with increased expression of BCL-2, BCL-X-L, and MCL-1. However, twenty-eight day long-term BCL-2 blockade following T cell-depleted bone marrow transplantation did not lead to changes in the global T cell landscape. Despite the lack of changes in T cell proportions, animals treated with venetoclax developed CD8(+) and CD4(+) T cells with high levels of BCL-2 and were more resistant to apoptotic stimuli following expansion post-transplant. Further, we demonstrate through RNA profiling that T cells adapt while under BCL-2 blockade post-transplant and develop a more activated genotype. Taken together, these data emphasize the importance of evaluating how BH3 mimetics affect the immune system in different treatment modalities and disease contexts and suggest that venetoclax should be further explored as an immunomodulatory compound.

Automated summary

BH3 mimetics, particularly the BCL-2 specific inhibitor venetoclax (ABT-199), have shown potential as anti-cancer therapeutics and also impact the immune system, particularly T cell subsets. Short-term BCL-2 inhibition leads to changes in T cell populations towards a more memory cell state, while long-term blockade does not significantly alter T cell landscape.