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.

doi:10.3233/blc-189029

Cited by 3 publications

(5 citation statements)

References 23 publications

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“…For example, the abundance of TLSs increases in advanced stages (II-IV) compared with stage I gastric cancer (171 patients analysed) 33 . A pilot study (28 patients) indicated that TLSs were more common in high-grade muscle-invasive bladder cancer than in the non-muscle-invasive cancers 91 . In breast cancer, high-grade tumours were found to be twice more prone to exhibit TLSs than low-grade tumours, and the most aggressive tumour grade, grade 3, is an independent predictor for TLS formation in patients with human epidermal growth factor receptor 2 (HER2; also known as ERBB2) − tumours 66,92,93 .…”

Section: Tlss During Tumour Progression the Link Betweenmentioning

confidence: 99%

Tertiary lymphoid structures in the era of cancer immunotherapy

2019

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Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.

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Section: Tlss During Tumour Progression the Link Betweenmentioning

confidence: 99%

Tertiary lymphoid structures in the era of cancer immunotherapy

2019

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“…In addition to lymphoplasmacytic and eosinophilic inflammation, about 15% of all canine UCs presented with formations of one or several lymphoid follicles, typically located in peritumoural tissue. The presence of tertiary lymphoid structures (TLSs) has been reported to occur in bladder and other types of cancer (Koti et al, 2017). Studies of the prognostic significance of TLSs in bladder cancer are rare.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of the prognostic significance of TLSs in bladder cancer are rare. Koti et al (2017) reported a poor prognostic significance of TLSs, which was seen more commonly in high-grade muscle invasive, compared with non-muscle invasive, bladder cancer. In the current series, no association between the presence and extent of TATE or TLSs, and muscle invasive growth, age, sex, neutering status or dog breed was identified.…”

Section: Discussionmentioning

confidence: 99%

A Fibromyxoid Stromal Response is Associated with Muscle Invasion in Canine Urothelial Carcinoma

Brot

Grau‐Roma

Stirling-Stainsby

et al. 2019

Journal of Comparative Pathology

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Canine urothelial carcinoma (UC) is the most common type of cancer of the lower urinary tract and tends to affect elderly neutered female dogs, with a high predisposition for Scottish terriers. Tumour stroma, inflammation and necrosis are poorly characterized in canine UC and their role as prognostic factors is unknown. The aims of this study were to (1) assess histologically 381 canine UCs, with emphasis on myxoid tumour stroma, inflammation and necrosis, and (2) assess possible associations between these features and the available epidemiological data as well as bladder wall muscle invasion. In 103 of 381 (27%) of cases, the stroma was mixed collagenous and myxoid (fibromyxoid), which was strongly associated with invasive growth of muscle (P <0.0001). Peritumoral and intratumoural inflammation was present in 308 of 345 (89%) and 287 of 381 (75%) of cases, respectively, and was mostly mild and lymphoplasmacytic. One hundred and fifteen of the 381 (30%) cases showed a variable eosinophilic inflammation, and 58 of 381 (15%) presented with formations of one or several lymphoid follicles. Twenty-four percent (91 of 381) of cases had tumour necrosis, which was typically mild. In 83 of 91 (91%) of cases, the necrosis was comedo-like.Moderate to severe tumour necrosis was associated with the presence of moderate to predominant fibromyxoid tumour stroma (P <0.02). The results of this study indicate that fibromyxoid stroma is common in canine UC and is a strong indicator for invasive growth of muscle, which is consistent with a poor prognosis. Based on histomorphology, tumour necrosis in canine UC is best described as comedonecrosis.

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“…22,23 Indeed, our previous report established an increase in TLS density and maturation with advanced stages of bladder cancer. 24 The average age of diagnosis for BC is ~73 years. Biological aging is accompanied by a decline in lymphopoiesis and depletion of naïve B cells from peripheral pools, with a simultaneous expansion of subpopulations such as atypical B cells (ABCs; also known as age-associated B cells).…”

Section: Introductionmentioning

confidence: 99%

“…22,23 Indeed, our previous report established an increase in TLS density and maturation with advanced stages of bladder cancer. 24…”

Section: Introductionmentioning

confidence: 99%

Atypical B cells mediate poor response to Bacillus Calmette Guérin immunotherapy in non-muscle invasive bladder cancer

Yolmo

Rahimi

Chenard

et al. 2022

Preprint

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Intravesical bacillus Calmette-Guerin (BCG) G immunotherapy is the gold standard treatment for patients with non-muscle invasive bladder cancer (NMIBC). Unfortunately, more than 50% patients experience early recurrence or progression. Increased intra-tumoral immune infiltration in pre-treatment tumors has been shown to associate with poor outcomes post BCG therapy. Specifically, we recently showed that high intra-tumoral B cell density was associated with early recurrence and progression of NMIBC. Here, we address a major knowledge gap in the role of BCG induced expansion of a B cell population, called atypical B cells (ABCs), in the context of age and sex, the two major variables in the pathophysiology of NMIBC. We first investigated whether pre-BCG TLSs associate with response to BCG. Using multiplex immunofluorescence and NanoString GeoMx digital spatial profiling-based characterization, we found higher density of tumor adjacent (TA) TLSs in patients categorized as BCG non-responders. Spatial proteomic profiling of 49 immune function and phenotype associated proteins revealed increased expression of immune exhaustion associated proteins in pre-BCG TLSs in tumors from both BCG responders and non-responders. It is established that patient age is a risk factor associated with poor outcomes in NMIBC and that biological aging associates with exhausted populations of immune cells. The expansion of ABCs is known to accompany biological aging and repetitive immunizations. We hypothesized that ABCs are recruited to the bladder mucosa due to repeated BCG instillations in the induction phase and dampen local anti-tumor immunity in patients deemed as BCG non-responders. Using the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen induced murine model, we investigated the role of B cells in BCG response in aging mice. Bladder local and systemic immune alterations were characterized at post BCG therapy with or without B cell depletion. Since B cells exhibit significant shifts with biological aging in a sex associated manner, we used the four-core genotype mouse model to determine such differences following repeated treatment with BCG. BCG treatment in combination with B-cell depletion led to distinct bladder immune microenvironment states and systemic immune profiles. Overall, this study demonstrates the significant role of ABCs in disease progression and that the B cell infiltrated pre-BCG therapy TA-TLSs reflect a systemically exhausted B cell functional state in patients deemed as BCG non-responders. Findings from this study provide the first evidence suggesting the role of B cells/ABCs in BCG response and will inform future translation to development of therapies targeting the B cell exhaustion axis.

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Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

Cited by 3 publications

References 23 publications

Tertiary lymphoid structures in the era of cancer immunotherapy

Tertiary lymphoid structures in the era of cancer immunotherapy

A Fibromyxoid Stromal Response is Associated with Muscle Invasion in Canine Urothelial Carcinoma

Atypical B cells mediate poor response to Bacillus Calmette Guérin immunotherapy in non-muscle invasive bladder cancer

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