Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer

Abstract

BackgroundThe aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.MethodsWe performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.ResultsVarying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.ConclusionThe immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

The prognostic value and molecular properties of tertiary lymphoid structures in oesophageal squamous cell carcinoma

“…However, Masuda et al. 31 recently showed that the maturity, spatial distribution and prognostic impact of TLSs were significantly different between the two types of genitourinary cancers, clear‐cell renal cell cancer and bladder cancer, which suggests that the effects of TLSs on tumours were tumour type specific. We found that only the presence of mature TLSs predicted better survival in ESCCs, which is similar to pancreatic cancers, 32 lung squamous cell carcinomas 33 and colorectal cancers.…”

“…The existence of TLSs correlated with patient survival in endometrial cancers, 27 head and neck squamous cell carcinomas, 28 metastatic melanomas 29 and non-functional pancreatic neuroendocrine tumours, 30 regardless of their maturation status. However, Masuda et al 31 recently showed that the maturity, spatial distribution and prognostic impact of TLSs were significantly different between the two types of genitourinary cancers, clear-cell renal cell cancer and bladder cancer, which suggests that the effects of TLSs on tumours were tumour type specific. We found that only the presence of mature TLSs predicted better survival in ESCCs, which is similar to pancreatic cancers, 32 lung squamous cell carcinomas 33 and colorectal cancers.…”

The roles of tertiary lymphoid structures in chronic diseases

“…The maturation stage of TLSs in cancer varies from B cell aggregates to organized structures with germinal centres 42,96 . In untreated lung 40,41 , colorectal 83 and bladder cancer 100 , mature, germinal centre-positive TLSs are a positive prognosticator of survival, whereas immature TLSs have either no association or a weak association with survival. In hepatocellular carcinoma, mature TLSs correlate with improved survival [101][102][103] , whereas immature TLSs serve as survival niches for tumour progenitor cells and confer a worse prognosis 104 .…”

Impact of interaction networks of B cells with other cells on tumorigenesis, progression and response to immunotherapy of renal cell carcinoma: A review

“…In lung squamous cell carcinoma, TLS are the independent prognostic marker and their development can be affected by chemotherapy and steroids ( 91 ). Interestingly, between different types of genitourinary cancer, one study showed that TLS displayed a distinct status in terms of the clinical outcome and immunogenomic profile ( 92 ). Researchers showed that the TLS detected in RCC cohort were less mature, contributing to poor outcomes, while in bladder cancer cohort, TLS were more mature with GC structures and associated with better outcomes ( 92 ).…”

“…Interestingly, between different types of genitourinary cancer, one study showed that TLS displayed a distinct status in terms of the clinical outcome and immunogenomic profile ( 92 ). Researchers showed that the TLS detected in RCC cohort were less mature, contributing to poor outcomes, while in bladder cancer cohort, TLS were more mature with GC structures and associated with better outcomes ( 92 ). Another study certificated that in three gradual levels of immune infiltration of ccRCC clusters, higher abundance of T cells and TLS, suggesting an immune-enriched TME, was related to poor clinical outcome ( 93 ).…”