A new study shows that tumours of patients with non-muscle-invasive bladder cancer (NMIBC) who do not respond to BCG therapy have elevated programmed cell death 1 ligand 1 (PD-L1) expression that is co-localized with CD8+ cells. The data show that intrinsic resistance to BCG might be caused by pretreatment adaptive immune responses and immune exhaustion.

Failure of intravesical BCG therapy occurs in ~50% of patients, and multiple studies have been investigating possibilities to predict BCG response to enable early treatment with alternative agents. “In this study, we aimed to understand how immune checkpoint activation might mitigate BCG response and thereby affect response to immune checkpoint inhibitors in NMIBC,” explains Max Kates from The Johns Hopkins School of Medicine, first author of the new paper. “We used tumour specimens before and after therapy from a large cohort of patients who underwent BCG treatment for NMIBC to understand how resistance is implicated in the mechanism of action of BCG.”

The cohort comprised samples from 31 BCG responders and 32 BCG nonresponders of whom 13 relapsed and 5 progressed to muscle-invasive disease. Using immunohistochemical full slide review and a combined positivity score method, the researchers found PD-L1 expression in 0–4% of responders but 25–28% of nonresponders (P < 0.01) before treatment. In all PD-L1+ samples, PD-L1+ cells and CD8+ cells co-localized and the density of CD8+ cells was increased in PD-L1+ areas. Furthermore, in nonresponders before BCG therapy, CD4+ cell counts were low in those who were PD-L1+ (12%) and high in those who were PD-L1– (50%, P < 0.01). Comparison of samples from nonresponders before and after BCG therapy showed no changes in immune-associated gene expression, numbers of CD4+ or FOXP3+ cells and PD-L1 expression; however, CD8+ cell counts were increased after BCG in samples from both responders and nonresponders (P = 0.017).

intrinsic resistance to BCG might be caused by pretreatment adaptive immune responses and immune exhaustion

“We found that adaptive immune resistance through the PD-L1 pathway is implicated in a subset of patients with recurrence after BCG, suggesting that these patients might benefit from combination therapy of PD-L1 inhibitors plus BCG,” concludes Kates. “The implications are that perhaps ~25% of patients with BCG resistance may ultimately have durable responses through combinatorial therapy.”