Intratumoral PD1(+)CD38(+)Tim3(+) CD8(+) T Cells in Pre-BCG Tumor Tissues Are Associated with Poor Responsiveness to BCG Immunotherapy in Patients with Non-Muscle Invasive Bladder Cancer

Intravesical immunotherapy with Bacillus Calmette–Guerin (BCG) is a standard of care therapy for non-muscle invasive bladder cancer (NMIBC), which accounts for about 75% of newly diagnosed urothelial cancer. However, given the frequent recurrence and progression, identification of a pre-treatment biomarker capable of predicting responsiveness to BCG in NMIBC is of utmost importance. Herein, using multiparametric flow cytometry, we characterized CD8(+) T cells from peripheral blood and tumor tissues collected from 27 pre-BCG patients bearing NMIBC to obtain immune correlates of bladder cancer prognosis and responsiveness to BCG therapy. We observed that intratumoral CD8(+) T cell subsets were highly heterogenous in terms of their differentiation state and exist at different proportions in tumor tissues. Remarkably, among the different CD8(+) T cell subsets present in the tumor tissues, the frequency of the terminally exhausted-like CD8(+) T cell subset, marked as PD1(+)CD38(+)Tim3(+) CD8(+) T cells, was inversely correlated with a favorable outcome for patients and a responsiveness to BCG therapy. Moreover, we also noted that the intratumoral abundance of the progenitor exhausted-like PD1(+)CD8(+) T cell subset in pre-BCG NMIBC tumor tissues was indicative of better recurrence-free survival after BCG. Collectively, our study led to the identification of biomarkers that can predict the therapeutic responsiveness of BCG in NMIBC.