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

Abstract

IntroductionMuscle-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.MethodsRNAseq 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.ResultsOverall, 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.DiscussionThis 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.

Distinct Infiltration of T Cell Populations in Bladder Cancer Molecular Subtypes

“…Bladder cancer molecular subtyping is a stratification system with higher resolution, and we show that the median immune infiltration was highest in the Ba/Sq subtype, followed by the luminal subtypes GU and Uro, which is in line with previous findings [ 15 , 33 , 34 ]. While MIBC comprises tumors of the Uro, Ba/Sq, and GU subtypes, the Uro subtype is by far the most common subtype among NMIBCs.…”

Effects of combined radiotherapy with immune checkpoint blockade on immunological memory in luminal-like subtype murine bladder cancer model

“… 32 In humans, TCGA data analysis of BCR and TCR sequencing suggests basal/squamous (Ba/sq) tumors and stroma-rich tumors infiltrating lymphocytes are more clonally expanded than in the luminal subtype. 33 Nevertheless, retrospective analysis of the ImVigor210 trial also highlights that overall high immune infiltration (based on an immune gene score) in both ba/sq and luminal MIBC tumors correlate with the lowest response rates to immunotherapy. 34 This hints that while efficient T cell responses and recall responses are required for potent anti-tumor immunity, factors intrinsic to the TME of MIBC luminal tumors prevent the expansion of functionally adequate T cells.…”

Exploring the potential of the TCR repertoire as a tumor biomarker (Review)

“…In MIBC, basal/squamous-like and stroma-rich subtypes exhibited high TCR richness and diversity, which were associated with a good prognosis. However, no changes in TCR richness or diversity were observed for the luminal subtype ( 83 ).…”

“…Furthermore, the limitations of the TCR repertoire as a biomarker are considered, such as the complexity and high cost of testing; the reasons and common clinical countermeasures are also briefly discussed. The present review also provides updates on recent research advancements in the development and application of TCR repertoires in tumors including thyroid cancer ( 98 ), MIBC ( 83 ), HGSOC ( 82 ), advanced or metastatic NSCLC ( 79 ), PDAC ( 72 ) and PSCC ( 36 ), and their associations with tumor immunotherapy, diagnosis and prognosis.…”