Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Damrauer, Jeffrey S.; Roell, Kyle; Smith, Markia A.; Sun, Xuezheng; Kirk, Erin L.; Hoadley, Katherine A.; Benefield, Halei C.; Iyer, Gopakumar V.; Solit, David B.; Milowsky, Matthew I.; Kim, William Y.; Nielsen, Matthew E.; Wobker, Sara E.; Dalbagni, Guido; Al‐Ahmadie, Hikmat; Olshan, Andrew F.; Bochner, Bernard H.; Furberg, Helena; Troester, Melissa A.; Pietzak, Eugene J.

doi:10.1158/1078-0432.ccr-21-0205

“…Differences in methodologies and the interpretation of earlier data resulted in several molecularly defined classifications currently available [13,20,28,[31][32][33][34][35][36][37][38]. Figure 1 depicts how molecular classifications of bladder cancer have evolved over the years.…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

López-Beltrán

¹

,

Blanca

²

,

Cimadamore

³

et al. 2021

Cancers

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Molecular classification of bladder carcinoma is a relevant topic in modern bladder cancer oncology due to its potential to improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation of molecular classification in practice is typically limited due to the high complexity of the required technology, the elevated costs, and the limited availability of this technology worldwide. We have conducted a gene expression analysis using a four-gene panel related to luminal and basal subtypes in a series of 91 bladder cancer cases. NanoString-based gene expression analysis using typically luminal (GATA3+/KRT20+) and basal markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial bladder carcinoma samples as luminal, basal, and a third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three categories were meaningful in terms of overall cancer-specific survival (p < 0.0001) or when classified as conventional urothelial carcinoma and variant histology urothelial carcinoma (p < 0.0001), NMIBC vs. MIBC (p < 0.001), or by AJCC stage category Ta (p = 0.0012) and T1 (p < 0.0001) but did not reach significance in T2-T4 (p = 0.563). PD-L1 expression (low vs. high) was also different according to molecular subtype, with high PD-L1 expression mostly seen in basal and null subtypes and carcinomas with variant histology (p = 0.002). Additionally, the luminal subtype was enriched in NMIBC with favorable cancer-specific survival (p < 0.0001). In contrast, basal and null subtypes resulted in aggressive MIBC tumors with shorter cancer-specific survival (p < 0.0001), some of which presented variant histology. In conclusion, a comprehensive evaluation of a gene classifier related to molecular taxonomy using NanoString technology is feasible. Therefore, it might represent an accessible and affordable tool in this rapidly expanding area of precision genomics.

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“…This link might explain the observed correlation to exhaustion through BCG-induced overactivation of the already active immune system. To the contrary, FGFR3 mutations have been linked to non-inflamed tumors suggesting a role of FGFR3 in T-cell exclusion in BC 32,33 . This may result in an exhaustion-protective role of FGFR3 mutations explaining the correlation to low post-BCG exhaustion.…”

Section: Discussionmentioning

confidence: 99%

“…mutations have been linked to non-inflamed tumors suggesting a role of FGFR3 in T-cell exclusion in BC 32,33 . This may result in an exhaustion-protective role of FGFR3 mutations explaining the correlation to low post-BCG exhaustion.…”

Section: Discussionmentioning

confidence: 99%

Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer

Strandgaard

¹

,

Lindskrog

²

,

Nordentoft

³

et al. 2022

Preprint

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BackgroundThe functional status of immune cells within the tumor microenvironment and tumor characteristics may explain Bacillus Calmette-Guérin (BCG)-failure in high-risk non-muscle invasive bladder cancer (NMIBC).ObjectiveTo characterize molecular correlates of BCG-failure using a multiomics approach.Design, Setting, and ParticipantsBCG-treated NMIBC patients (n=156) were included. Metachronous tumors were analyzed using RNA-sequencing (n=170) and whole exome sequencing (n=198). Urine samples were analyzed for immune-oncology related proteins (n=190), and tumor-derived DNA (tdDNA; n=192).Outcome Measurement and Statistical AnalysisPrimary endpoint was BCG-failure. Cox regression, Wilcoxon Rank Sum test, t-test or Fisher’s exact test were used.Results and LimitationsBCG caused activation of the immune system regardless of clinical response; however, immune-inhibitory proteins were observed in the urine of BCG-unresponsive patients post-treatment (CD70, PD1, CD5). BCG-failure was associated with post-BCG T-cell exhaustion (p=0.0021). Pre-BCG tumors from patients with post-BCG T-cell exhaustion were characterized by high expression of cell division and immune-related genes. A high post-BCG exhaustion prediction score in pre-BCG tumors was associated with worse post-BCG high-grade recurrence free survival (HGRFS), reflecting BCG-failure (p=0.0084). Pre-BCG tumors of class 2a and 2b were likewise associated with worse post-BCG HGRFS(p=0.0023). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p=0.023) and mutations in MUC4 (p=0.0007). Finally, absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p=0.028). The retrospective design, lack of maintenance BCG, and partial overlap in analyses are limitations to the study.ConclusionsBCG failure may be caused by T-cell exhaustion. Tumor subtype and Pre-BCG tumor characteristics may identify patients at high risk of BCG-failure prior to treatment. Urinary measurements have the potential to be used as a real-time assessment of treatment response.Patient SummaryA dysfunctional immune response to BCG therapy may explain lack of response to the treatment.

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“…With the rise and popularization of high-throughput sequencing, more and more biomarkers associated with the prognosis or drug response of BLCA have been discovered [8,9]. The screened biomarkers not only helped to evaluate the clinical outcomes but also provided the clues to study the potential mechanisms of BLCA, such as ferroptosis [10], autophagy [11], and N6-methyladenosine (m6A) modification [12].…”

Section: Introductionmentioning

confidence: 99%

An Immunosenescence-Related Gene Signature to Evaluate the Prognosis, Immunotherapeutic Response, and Cisplatin Sensitivity of Bladder Cancer

Zhou

¹

,

Liang

²

,

Tian

³

et al. 2022

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Immunosenescence refers to the immune system undergoing a series of degenerative changes with advancing age and is tightly associated with the initiation and progression of cancers. However, the immunosenescence-related genes as critical biomarkers for bladder cancer (BLCA) have not been systematically analyzed. We retrieved the immunosenescence-related genes from the public database and verified their association with hallmarks of immunosenescence based on The Cancer Genome Atlas (TCGA) cohort. Through gene pairing, Lasso, and univariate Cox regression, an 8-gene pair model was constructed to evaluate the overall survival of BLCA, which was then validated in the training cohort ( P < 0.001 , n = 396 ), two external validation cohorts ( P < 0.05 , n = 165 ; P < 0.001 , n = 224 ), and local samples ( P < 0.05 , n = 10 ). We also downloaded the clinical information and gene expression matrices of other 32 different cancers from TCGA. The established model showed significant predictive value for the prognosis in 15 cancers ( P < 0.05 ). The risk model could also serve as a promising predictor for immunotherapeutic response, which has been verified by the TIDE algorithm ( P < 0.05 ), IMvigor210 dataset ( P < 0.01 , n = 298 ), and other two datasets correlated with immunotherapy ( P < 0.05 , n = 56 ; P = 0.17 , n = 27 ). The TCGA dataset, in vitro cell experiments, and pan-cancer analysis displayed that the gene signature was associated with cisplatin sensitivity ( P < 0.05 ). Overall, we proposed a novel immunosenescence-related gene signature to predict prognosis, immunotherapeutic response, and cisplatin sensitivity of BLCA, which were validated in different independent cohorts, local samples, and pan-cancer analyses.

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Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Cited by 31 publications

References 41 publications

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer

An Immunosenescence-Related Gene Signature to Evaluate the Prognosis, Immunotherapeutic Response, and Cisplatin Sensitivity of Bladder Cancer

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