Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

Koti, Madhuri; Xu, Amanda Shuo; Ren, Kevin; Visram, Kash; Ren, Runhan; Berman, David M.; Siemens, D. Robert

doi:10.3233/blc-170120

Cited by 52 publications

(30 citation statements)

References 16 publications

(3 reference statements)

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“…TLTs typically elaborate functions that otherwise only occur within the secondary lymphoid organs, but TLTs are localized to the site of inflammation and immune response 15 , 16 . Lymphoid aggregates have been reported in a few models of chronic bacteriuria and bladder cancer but remain poorly characterized and have thus far not been reported in unperturbed bladders 18 , 19 , 33 . Since bTLTs are specifically found in aged bladders, they could facilitate inflamm-aging within the bladder tissue and significantly alter immune responses to a variety of stimuli.…”

Section: Resultsmentioning

confidence: 99%

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

et al. 2020

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Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA + plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT form, as aged germfree mice harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.

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Section: Resultsmentioning

confidence: 99%

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

et al. 2020

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“…The cytotoxic T cell response is driven by cancer-associated antigens 29 and bladder cancer ranks among cancers with the highest mutation burden. 30 In the present study, high densities of CD8 + T cells in both TURB and cystectomy specimens were found to be independently associated with a prolonged TTR.…”

Section: Discussionmentioning

confidence: 99%

“…33 The presence of lymphoid aggregates indicates an ongoing clonal B cell expansion and has gained attention due to their prognostic role in some cancers. 29,34 Lymphoid aggregates have been found to be more common in high-grade MIBC than in low-grade non-MIBC. 29 But their prognostic value has not yet been evaluated.…”

Section: Discussionmentioning

confidence: 99%

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Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer: a comparative study of transurethral resection and cystectomy specimens

et al. 2019

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In patients with muscle invasive bladder cancer (MIBC), neoadjuvant chemotherapy (NAC) prior to radical cystectomy has improved survival but there is an urgent unmet need to identify prognostic and predictive biomarkers to stratify patients who will benefit from treatment. This study aimed to examine the composition of tumor-infiltrating immune cells in MIBC, with particular reference to the clinical outcome and the potential modifying effect of NAC. To this end, the expression of CD8 + and FoxP3 + T cells, CD20 + B cells, PD-1 + and PD-L1 + immune cells and PD-L1 + tumor cells was evaluated by immunohistochemistry on tissue microarrays with paired transurethral resection (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, 65 of whom had received NAC. Kaplan-Meier and Cox regression analyses were applied to assess the impact of investigated cell subsets on time to recurrence (TTR). In cystectomy specimens, high infiltration of the investigated immune cell populations, but not PD-L1 + tumor cells, were independently associated with a prolonged TTR, whereas in TURB specimens, this association was only seen for CD8 + lymphocytes. An additive beneficial prognostic effect of NAC was seen for the majority of the cell subsets but there was no significant interaction between any immune marker and NAC in relation to TTR. Furthermore, no differences in cell densities prior to NAC treatment were observed between complete and non-complete responders, or pre-and posttreatment in non-complete responders. In conclusion, immune cell infiltration provides important prognostic information in both pre-and postsurgical samples of MIBC, independently of NAC.

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“…For example, isolated lymphoid follicles (intestinal TLT) in aged mice have altered 58 cellular compositions and produce more IgA compared to young mice (27), and inducible 59 bronchus-associated lymphoid tissue (lung TLT) forms more robustly in response to cigarette 60 smoke in aged mice compared to young mice (28). Whether aging affects immunity in the bladder 61 mucosa is not known. Since both infectious and non-infectious chronic bladder inflammation is 62 highly prevalent in older women, age-associated disruption of immune homeostasis in the bladder 63 may mediate inflammatory pathology and lower urinary tract symptoms.…”

Section: Introductionmentioning

confidence: 99%

Tertiary lymphoid tissue develops during normal aging in mice and humans

Ligon

Wang

Jennings

et al. 2019

Preprint

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One Sentence Summary: Mice develop bladder tertiary lymphoid tissue (bTLT) during aging that is dependent on TNF and independent of urinary tract infection.ABSTRACT 1 Aging has multifaceted effects on the immune system in the context of systemic responses 2 to specific vaccines and pathogens, but how aging affects tissue-specific immunity is not well-3 defined. Chronic bladder inflammation is highly prevalent in older women, but mechanisms by 4 which aging promotes these pathologies remain unknown. Here we report distinct, age-5 associated changes to the immune compartment in the otherwise normal female (but not in male) 6 mouse urinary bladder and parallel changes in older women with chronic bladder inflammation. 7 In aged mice, the bladder epithelium became more permeable, and the homeostatic immune 8 landscape shifted from a limited, innate immune-predominant surveillance to an inflammatory, 9 adaptive immune-predominant environment. Strikingly, lymphoid cells were organized into tertiary 10 lymphoid tissues, hereafter named bladder tertiary lymphoid tissue (bTLT). Analogous bTLTs 11 were found in older women, many of whom had a history of recurrent urinary tract infection (UTI). 12Aged mice responded poorly to experimental UTI, experiencing spontaneous recurrences at 13 higher rates than young mice. However, bTLT formation was dependent on aging and 14 independent of infection. Furthermore, bTLTs in aged mice played a role in de novo antibody 15 responses and urinary IgA production by recruitment of naive B cells that form germinal centers 16 and mature into IgA-secreting plasma cells. Finally, TNF was a key driver of bTLT formation, as 17 aged TNF -/mice lacked bTLTs. Both aged TNF -/and wild type mice exhibited increased 18 bladder permeability, suggesting that epithelial dysfunction may be an upstream mediator of 19 chronic, age-associated bladder inflammation. Thus, bTLTs arise as a function of age and may 20 underlie chronic, age-associated bladder inflammation. Our model establishes a platform for 21 further investigation of age-association tissue inflammation and translation to new treatment 22 strategies. 24Immune dysfunction during aging is characterized by chronic, low-grade inflammation 25 coupled with ineffective responses to pathogens. Aging is also the strongest risk-factor for 26 numerous chronic diseases, including cardiovascular disease, neurodegeneration, osteoarthritis, 27 and cancers. While these diseases are all linked by chronic inflammation, immune responses vary 28 by tissue, resulting in tissue-specific inflammation and dysfunction. Older women (50+) are highly 29 susceptible to bladder disorders including overactive bladder/urge incontinence (OAB), interstitial 30 cystitis/bladder pain syndrome (IC/BPS), and recurrent urinary tract infections (rUTIs) (1-5). 31These disorders all have a chronic inflammatory component as well as overlapping symptoms, 32 known as lower urinary tract symptoms (6, 7). How and why bladder disorders and bladder 33 inflammation become more prevalent with ...

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Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

Cited by 52 publications

References 16 publications

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα-dependent but microbiota-independent tertiary lymphoid tissue formation

Clinical impact of T cells, B cells and the PD-1/PD-L1 pathway in muscle invasive bladder cancer: a comparative study of transurethral resection and cystectomy specimens

Tertiary lymphoid tissue develops during normal aging in mice and humans

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