Cancers of mature T cells, such as T cell non-Hodgkin lymphoma (NHL), are aggressive and resistant to treatment. Two new papers provide insight into the future treatment of mature T cell cancers. Wartewig and colleagues demonstrate that PDCD1, which encodes programmed cell death protein 1 (PD1), is a haploinsufficent tumour suppressor in this cancer, suggesting that immuno-oncology strategies inhibiting PD1 could, unlike in other tumours, cause T cell NHLs to expand. In a second paper, Maciocia and colleagues exploit the clonal nature of tumours to specifically target one of the T cell receptor β-chain constant domains, TRBC1, using a chimeric antigen receptor (CAR) T cell approach.
Wartewig and colleagues began by generating mice that express a transgene that encodes a fusion protein, ITK–SYK, which is produced by a translocation found in human T cell NHL. ITK–SYK has constitutive tyrosine kinase activity and promotes oncogenic signalling from T cell receptor (TCR) pathways. Expression of the ITK–SYK transgene in CD4+ cells resulted in fully penetrant, aggressive, clonal T cell lymphomas after 200–250 days, following an initial cell expansion and contraction phase.
This delay in tumorigenesis suggested that additional alterations are required. Using a transposon mutational screen, the authors identified PDCD1 as the most common gene that, if disrupted, leads to rapid transformation. Indeed, in a meta-analysis of five published studies of human T cell lymphomas, PDCD1 was altered in 36 of 158 cases.
“deletion of one or both copies of PDCD1 reduced the time to the formation of lethal infiltrative lymphomas”
In mice that express ITK–SYK in T cells, deletion of one or both copies of PDCD1 reduced the time to formation of lethal infiltrative lymphomas to about 1 week (Pdcd1−/−) or 1 month (Pdcd+/−). Similarly, treating mice expressing ITK–SYK with inhibitors of PD1 or programmed death 1 ligand 1 (PDL1), a recently established class of immuno-oncology agent, led to an immediate and lethal expansion of ITK–SYK+ cells.
In T cell lines, ITK–SYK drives PD1 expression. Normally, PD1 ligation dampens oncogenic signalling by increasing levels of phosphatase and tensin homologue (PTEN), thus providing a negative feedback loop: PTEN counteracts the effects of phosphoinositide 3-kinase (PI3K), a key downstream component of TCR signalling that is engaged by ITK–SYK. Treatment of ITK–SYK-expressing mice with the PI3K inhibitor idelalisib significantly extended their lifespan, underscoring the importance of this signalling pathway and also providing a potential therapeutic avenue.
In another paper, Maciocia and colleagues generated CAR T cells that target TRBC1, but not TRBC2, to treat mature T cell cancers. Each T cell (and therefore each T cell cancer) irreversibly selects either TRBC1 or TRBC2 to incorporate into TCRs. Approximately 35% of normal and virus-specific T cells express TRBC1, and 65% express TRBC2. Thus, targeting tumours that express TRBC1 should deplete the tumour cells but leave enough T cells to fight infections.
T cells transduced with TRBC1-specific CAR constructs were able to kill TRBC1+ cell lines, and allogenic or autologous CAR T cells were able to kill TRBC1+ primary human malignant cells but not normal TRBC2+ T cells. These CAR T cells were also effective in immunodeficient mice engrafted with TRBC1+ T cells. A clinical trial of anti-TRBC1 CAR T cells for TRBC1+ mature T cell malignancies is due to commence in 2018.
These findings suggest new therapeutic avenues for the treatment of mature T cell malignancies, and also caution against the use of PD1 or PDL1 inhibitors in these cancers.
Wartewig, T. et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature http://dx.doi.org/10.1038/nature24649 (2017)
Maciocia, P. M. et al. Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat. Med. http://dx.doi.org/10.1038/nm.4444 (2017)
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Cully, M. Strategies for mature T cell cancers. Nat Rev Drug Discov 17, 15 (2018). https://doi.org/10.1038/nrd.2017.254