Claudin-low bladder tumors are immune infiltrated and actively immune suppressed

Kardos, Jordan; Chai, Shengjie; Mose, Lisle E.; Selitsky, Sara R.; Krishnan, Bhavani; Saito, Ryoichi; Iglesia, Michael D.; Milowsky, Matthew I.; Parker, Joel S.; Kim, William Y.; Vincent, Benjamin G.

doi:10.1172/jci.insight.85902

Cited by 188 publications

(213 citation statements)

References 38 publications

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“…Neoantigen-containing proteins in the B16F10 mouse model were predicted in silico using our previously described pipeline 24, 25 . Note that only combinations of adjacent missense mutations supported on the same read of WES data were considered and only neoantigens predicted in four of four biological replicates were included in our analysis.…”

Section: Methodsmentioning

confidence: 99%

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Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology.

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Section: Methodsmentioning

confidence: 99%

“…To determine whether AC-NPs captured tumor-specific antigens, we performed an in silico analysis on our mass spectrometry data to determine if any of the captured proteins contain neoantigens expressed by B16F10 cells 24,25 . Neoantigens are tumor specific antigens created by somatic mutations 26 .…”

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confidence: 99%

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

et al. 2017

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“…In the phase II trial that led to Food and Drug Administration approval of the drug, patients whose tumors belonged to TCGA cluster II obtained somewhat more benefit than patients whose tumors belonged to the other subtypes, and patients with “papillary” (cluster I) tumors derived little benefit, if at all [79]. Importantly, immune infiltration and tumor PDL1 expression are actually highest in TCGA cluster IV, which corresponds to a subset of “mesenchymal” basal tumors [80], and this connection between EMT and immune infiltration and tumor PDL1 expression was observed across solid tumors in a recent pan-cancer analysis [81]. Therefore, even though TCGA cluster IV tumors are heavily infiltrated with lymphocytes, the T cells appear to be more actively suppressed than are the T cells in the tumors that belong to TCGA cluster II luminal subtype [80], which could explain why cluster IV tumors are somewhat less sensitive to immune checkpoint blockade.…”

Section: Evidence Synthesismentioning

confidence: 99%

“…Importantly, immune infiltration and tumor PDL1 expression are actually highest in TCGA cluster IV, which corresponds to a subset of “mesenchymal” basal tumors [80], and this connection between EMT and immune infiltration and tumor PDL1 expression was observed across solid tumors in a recent pan-cancer analysis [81]. Therefore, even though TCGA cluster IV tumors are heavily infiltrated with lymphocytes, the T cells appear to be more actively suppressed than are the T cells in the tumors that belong to TCGA cluster II luminal subtype [80], which could explain why cluster IV tumors are somewhat less sensitive to immune checkpoint blockade. It could be noteworthy that atezolizumab provided maximal benefit in a portion of the tumors that belonged to the subtype that had been previously defined as being more resistant to conventional chemotherapy [71,77].…”

Section: Evidence Synthesismentioning

confidence: 99%

Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset

et al. 2017

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Context Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. Objective The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. Evidence acquisition We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA’s bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. Evidence synthesis The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. Conclusions The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Patient summary Our observation showed that some of subtype-enriched mutations and copy number variations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.

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“…In particular, a subset of basal bladder cancers (claudin-low, TCGA cluster IV) appear to be highly immune infiltrated, yet express high levels of checkpoint molecules and other immunosuppressive biomarkers, which suggests therapeutic potential for checkpoint blockade in these patients. 18 Recent data from a phase II trial of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) also suggests that in the p53-like (TCGA Cluster II) subtype, there is a higher relative response to immunotherapy, which may be a viable strategy in this patient cohort that appears to be cisplatin-resistant. 19 Results of the CO-eXpression ExtrapolatioN (COXEN) trial (NCT02177695) will also be informative for both validation and discovery, as this trial will correlate gene expression profiles and DNA mutations with pathologic responses, survival, and multiple NAC regimens in prospective fashion.…”

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confidence: 99%

Pathways Forward in Candidate Selection for Systemic Therapy in Invasive Urothelial Cancer of the Bladder

Sundi¹

2016

Oncology &Amp; Hematology Review (US)

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49Urothelial carcinoma of the bladder (UCB) is a highly prevalent and lethal disease, with an estimated annual global incidence and mortality of 430,000 and 165,000, respectively.1 The vast majority of mortality from UCB is due to invasive cancers (invading the muscularis propria and beyond, ≥T2) and advanced disease stages (lymph node or distant metastases, N1-3 and M1). The historic gold standard curative treatment for locally invasive (T2-T3bN0M0) and locally advanced (T2-T4a, N1-3) is radical cystectomy (RC). 2 Randomized prospective trials have shown that there is a survival benefit when cisplatin-based neoadjuvant chemotherapy (NAC) is administered prior to RC (compared to RC alone). 3,4 However, the absolute survival benefit with NAC is small in magnitude (6-14% over five years) because only select patients respond to NAC.Taking into consideration significant toxicities that can result from systemic chemotherapy, an important challenge for oncologists treating UCB is to select patients who will actually benefit from NAC. Here, we will review contemporary patient selection strategies and emerging discoveries that may establish new strategies to select patients for NAC. AbstractNeoadjuvant chemotherapy (NAC) prior to radical cystectomy improves overall survival for patients with invasive bladder cancer, compared to patients undergoing radical cystectomy alone. However, only a subset of patients benefit from NAC. This editorial highlights recent and emerging developments that aim to identify optimal NAC candidates.

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Claudin-low bladder tumors are immune infiltrated and actively immune suppressed

Cited by 188 publications

References 38 publications

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset

Pathways Forward in Candidate Selection for Systemic Therapy in Invasive Urothelial Cancer of the Bladder

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