Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma

Hakozaki, Kyohei; Tanaka, Nobuyuki; Takamatsu, Kimiharu; Takahashi, Ryohei; Yasumizu, Yota; Mikami, Shuji; Shinojima, Toshiaki; Kakimi, Kazuhiro; Kamatani, Takashi; Miya, Fuyuki; Tsunoda, Tatsuhiko; Aimono, Eriko; Nishihara, Hiroshi; Mizuno, Ryuichi; Oya, Mototsugu

doi:10.1038/s41416-021-01559-8

Cited by 13 publications

(19 citation statements)

References 32 publications

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“…Comprehensive DNA methylation analysis was performed for 39 fresh-frozen tissue samples that matched the TMA samples in cohort A with the Infinium MethylationEPIC BeadChip (Illumina) according to the manufacturer’s protocol. 18 The data were assembled using GenomeStudio Methylation software (Illumina) after background subtraction and normalization. The methylation levels of CpG sites are represented as β values ranging from 0 (completely unmethylated) to 1 (completely methylated), reflecting the methylation level of an individual CpG site.…”

Section: Methodsmentioning

confidence: 99%

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

Masuda

Tanaka

Takamatsu

et al. 2022

J Immunother Cancer

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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.

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Section: Methodsmentioning

confidence: 99%

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

Masuda

Tanaka

Takamatsu

et al. 2022

J Immunother Cancer

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“…Hakozaki et al. recently reported a large-scale analysis of primary and metastatic RCC lesions ( 234 ). The investigators showed that combined GAS6/AXL scoring, obtained from IHC on tissue microarray (TMA) samples, was an independent marker of poor prognosis following surgery, proving superior to each staining alone.…”

Section: Axl and Related-time Components As Promising Biomarkers For ...mentioning

confidence: 99%

“…Although ethically questionable and complicated to implement in clinical practice, longitudinal sampling would be beneficial to advance our knowledge in this respect. The TIME is critical to effective therapy, and although the contribution of AXL or GAS6/AXL-related signatures in predicting ICI resistance remains unproven ( 133 , 234 ), it would be of great interest to study how surrogate markers of immune response in combination with such signatures could improve their predictive value. As observed in numerous cancer systems, associations between AXL, TGF-ß signaling, and reduced levels of MHC class I deserve to be further investigated.…”

Section: Axl and Related-time Components As Promising Biomarkers For ...mentioning

confidence: 99%

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

et al. 2022

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The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.

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“…Also, in renal cell carcinoma (RCC), Gas6 expression is found. Most studies measured Gas6 in clear cell RCC (ccRCC), but there are smaller cohorts of non-ccRCC [ 9 ]. Additionally, expression of Gas6 was associated with poorer survival [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Since RCC is not sensitive for chemotherapy, targeted therapies are warranted. Hakozaki et al discuss Gas6/Axl to be a target in RCC treatment [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Growth Arrest-Specific 6 in Chromophobe Renal Cell Carcinoma

et al. 2022

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Background: Overexpression of tumor-associated growth arrest-specific protein 6 (Gas6) is found in many tumor entities. The prognostic value of Gas6 in renal cell carcinoma (RCC), especially in non-clear cell RCC, is still unclear. Aim: The aim of the study was to evaluate the prognostic impact of Gas6 expression in a large cohort of patients with chromophobe RCC (chRCC). Material and Methods: Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Gas6 expression by immunohistochemistry. Results: Eighty-one chRCC patients were eligible for analysis; of these, 24 (29.6%) patients were positive for Gas6. No significant associations were found for Gas6 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Gas6− compared to Gas6+ (89.6% vs. 100.0%; p = 0.288) tumors. Conclusion: In chRCC, Gas6 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.

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Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma

Cited by 13 publications

References 32 publications

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

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

Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

Growth Arrest-Specific 6 in Chromophobe Renal Cell Carcinoma

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