Characterization of the tumor-infiltrating immune repertoire in muscle invasive bladder cancer.

INTRODUCTION

Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease with several taxonomic molecular subtypes showing different genetic, clinical, and epidemiological profiles. It has been suggested that MIBC-subtypes follow different tumorigenesis pathways playing decisive roles at different stages of tumor development, resulting in distinct tumor microenvironment containing both innate and adaptive immune cells (T and B lymphocytes). We aim to characterize the MIBC tumor microenvironment by analyzing the tumor-infiltrating B and T cell repertoire according to the taxonomic molecular subtypes.

METHODS

RNAseq data from 396 MIBC samples included in TCGA were considered. The subtype information was collected from the international consensus taxonomic classification describing six subtypes: Basal/Squamous-like (Ba/Sq), Luminal papillary (LumP), Luminal non-Specify (LumNS), Luminal unstable (LumU), Stroma-rich, and Neuroendocrine-like (NE-like). Using MiXCR, we mapped the RNA read sequences to their respective B-cell receptor (BCR) and T-cell receptor (TCR) clonotypes. To evaluate the BCR and TCR differences among subtypes, we compared diversity measures (richness and diversity) using a Wilcoxon test and we performed a network analysis to characterize the clonal expansion. For the survival analysis stratified by subtypes, Cox regression models adjusted for age, region, and pathological stage were performed.

RESULTS

Overall, we found different patterns of tumor-infiltrating immune repertoire among the different MIBC subtypes. Stroma-rich and Ba/Sq tumors showed the highest BCR and TCR infiltration while LumP showed the lowest. In addition, we observed that the Ba/Sq and Stroma-rich tumors were more clonally expanded than the Luminal subtypes. Moreover, higher TCR richness and diversity were significantly associated with better survival in the Stroma-rich and Ba/Sq subtypes.

DISCUSSION

This study provides evidence that MIBC subtypes present differences in the tumor microenvironment, in particular, the Ba/Sq and the Stroma-rich are related with a higher tumoral-infiltrating immune repertoire, which seems to be translated into better survival. Determining the causes of the different tumoral-infiltrating immune repertoire according to the MIBC molecular subtypes will help to improve our understanding of the disease and the distinct responses to immunotherapy of MIBC.