Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer

Abstract

Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4+ T cells, CD8+ T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8+PD-1+ T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8+PD-1- T cells and non-Treg CD4+FOXP3- T cells; but increased exhausted CD8+PD-1+ T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1+CD8+ T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

“…BCG-based immunotherapy remains ineffective in some NMIBC patients, although efforts have been made to characterize the response, giving the opportunity of an early selection of strategies for the patients who do not benefit from BCG treatment [99]. The expression of several biomarkers related to immune response correlate with resistance to BCG treatment; immune checkpoint inhibitors are complements for the therapy, in particular PD-L1 inhibitors, such as atezolizumab, nivolumab, pembrolizumab, avelumab, and durvalumab [94].…”

Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes

“…Peripheral blood immune profiles have been associated with different outcomes in bladder cancer patients and may have clinical utility for NMIBC prognosis [ 8 – 13 ]. For instance, in NMIBC, patients with elevated neutrophil-to-lymphocyte ratio (NLR) had poorer cancer-specific survival than patients with lower NLR [ 9 – 11 ].…”

Intravesical High Dose BCG Tokyo and Low Dose BCG Tokyo with GMCSF+IFN α Induce Systemic Immunity in a Murine Orthotopic Bladder Cancer Model

“…Bladder tissue analysis in patients receiving BCG immunotherapy have shown a correlation between exhaustion of T cells and poor response to therapy [ 14 , 15 ]. Following intravesical therapy, there were shown to be increased T cells to BCG antigens [ 16 ]; however, tumor antigen specific T cells have not yet been confirmed.…”