T-cell exhaustion tied to post-BCG recurrence in bladder cancer

In patients with nonmuscle-invasive bladder cancer (NMIBC), high-grade (HG) recurrence after bacillus Calmette-Guérin (BCG) treatment is associated with T-cell exhaustion, according to a study.

“Our results highlight several correlates to post-BCG HG recurrence, and we showed that CD8 T-cell exhaustion may be a key factor,” the researchers said. “Taken together, these results could be used to guide clinical decision-making if validated in clinical trials.”

A total of 156 patients (median age 71 years, 79 percent men) who had received at least five instillations of BCG were included in the analysis, of whom 70 had HG recurrence. The primary endpoint of the study was HG recurrence after BCG treatment.

Urinary profile analysis included 124 patients, contributing a total of 190 samples collected within 4 months before and after BCG treatment. Comparing between 66 paired samples revealed that BCG treatment led to the upregulation of several proteins, including the C-X-C motif ligands 9, 11, and 10, and the programmed cell death protein 1 (PD-1). [Eur Urol 2022;doi:10.1016/j.eururo.2022.09.008]

Of note, those with HG recurrence after BCG demonstrated a spike in CD70 levels, which is indicative of an inhibited inflammatory T-cell response. Similarly, other immunoinhibitory proteins, including CD5, PD-1, and its cognate ligand, were also elevated in recurrent patients. In terms of biological function, HG recurrence was associated with elevations in the chemotaxis pathway (p=0.017), as well as disturbances in tumour immunity suppression (p=0.065).

The research team then conducted gene expression on 170 samples, of which 44 were collected after BCG treatment. RNA sequencing showed that after BCG treatment, those with HG recurrence had elevated immune infiltration score (p=0.046), dendritic cells (p=0.036), mast cells (p=0.043), and exhausted CD8 T cells (p=0.017).

In turn, a higher level of CD8 T cell exhaustion correlated with greater HG recurrence, both when measured before (p=0.056) and after (p=0.002) BCG treatment. Of note, all post-BCG tumours with extensive CD8 T cell exhaustion all demonstrated HG recurrence.

Comparing pre- and post-BCG gene expression, the researchers found that pathways related to the cell cycle and immune response were particularly enriched in pre-BCG tumours that would eventually show high levels of exhaustion after BCG treatment. These included genes involved in the G2M checkpoint (p<0.001), E2F targets (p<0.001), interferon gamma response (p<0.001), and inflammation (p<0.001).

Multivariate Cox regression analysis revealed that a post-BCG exhaustion prediction score, taking into account several differentially expressed genes between pre-BCG tumours, was significantly predictive of high-grade recurrence-free survival (p=0.018).

“Pre-BCG prediction of post-BCG CD8 T-cell exhaustion has the potential to identify patients at high risk of post-BCG HG recurrence, and urinary measurement of proteins and tumour-derived DNA could be used to monitor treatment response,” the researchers said. “If validated in clinical trials, this strategy could potentially improve treatment regimens for patients with high-risk NMIBC.”