The association between tumor mutational burden and prognosis is dependent on treatment context

Valero, Cristina; Lee, Mark; Hoen, Douglas R.; Wang, Jingming; Nadeem, Zaineb; Patel, Neal; Postow, Michael A.; Shoushtari, Alexander N.; Plitas, George; Balachandran, Vinod P.; Smith, J. Joshua; Crago, Aimeé M.; Roche, Kara C. Long; Kelly, Daniel; Samstein, Robert M.; Rana, Satshil; Ganly, Ian; Wong, Richard J.; Hakimi, A. Ari; Berger, Michael F.; Zehir, Ahmet; Solit, David B.; Ladanyi, Marc; Riaz, Nadeem; Chan, Timothy A.; Seshan, Venkatraman; Morris, Luc G.T.

doi:10.1038/s41588-020-00752-4

Cited by 185 publications

(142 citation statements)

References 28 publications

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“…Due to the high intrinsic resistance to conventional chemo-and radiotherapies and the rapid development of resistance to targeted therapy, immune checkpoint inhibitors (ICIs) have been one of the few effective therapies for RCC. Previous studies have reported that higher TMB is closely related to better OS after ICI treatment (Valero et al, 2021). The new findings in our study indicated that the signature may be a predictive biomarker to predict the efficacy of immunotherapy.…”

Section: Discussionsupporting

confidence: 68%

Analyzing and Validating the Prognostic Value of a TNF-Related Signature in Kidney Renal Clear Cell Carcinoma

Zhang

et al. 2021

Front. Mol. Biosci.

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Background: Kidney renal clear cell carcinoma (KIRC) has the highest incidence rate in renal cell carcinoma (RCC). Although bioinformatics is widely used in cancer, few reliable biomarkers of KIRC have been found. Therefore, continued efforts are required to elucidate the potential mechanism of the biogenesis and progression of KIRC.Methods: We evaluated the expression of tumor necrosis factor (TNF) family genes in KIRC, and constructed a prognostic signature. We validated the signature by another database and explored the relationship between the signature and progression of KIRC. We assessed the prognostic value, immune infiltration, and tumor mutation burden (TMB) of the signature in KIRC.Results: We selected four key genes (TNFSF14, TNFRSF19, TNFRSF21, and EDA) to construct the TNF-related signature. We divided the KIRC patients into high- and low-risk groups based on the signature. Patients with higher risk scores had shorter overall survival and worse prognosis. With another database, we validated the value of the signature. The signature was considered as an independent risk factor. A higher level of risk score was relevant to higher level of immune infiltration, especially T regulatory cells, CD8+ T cells, and macrophages. The signature was also associated with TMB scores, and it may have an effect on assessing the efficacy of immunotherapy.Conclusion: This is the first TNF-family-related signature of KIRC and we demonstrated its effectiveness. It played a significant role in predicting the prognosis of patients with KIRC. It also has the potential to become a powerful tool in guiding the immunotherapy of KIRC patients in clinical practice.

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Section: Discussionsupporting

confidence: 68%

Analyzing and Validating the Prognostic Value of a TNF-Related Signature in Kidney Renal Clear Cell Carcinoma

Zhang

et al. 2021

Front. Mol. Biosci.

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“…For example, we showed that in CRC high TMB is necessary but not sufficient to achieve durable benefit and that, above the critical threshold of hypermutated phenotype, even CRCs with very high TMB may not respond to treatment. This is different from lung cancer and melanoma where response always positively correlates with TMB 7,11 . It also suggests that, at least in CRC, a low TMB is a marker of resistance not because of a low neoantigenic load but because it is indicative of a different biology leading to immune cold tumours.…”

Section: Discussionmentioning

confidence: 58%

“…Surprisingly, in the discovery cohort DB-CRCs had a significantly lower TMB than nDB-CRCs ( Fig.1F). When adding further hypermutated CRCs from the validation cohort and published studies [7][8][9][10][11] , we observed no significant difference between DB-and nDB-CRCs (Fig.1G). Therefore, in CRC a TMB below 12 mutations/Mbp is a predictor of resistance to anti-PD1 immunotherapy while, above this threshold, it is no longer associated with response.…”

Section: Response Of Hypermutated Crcs Is Associated With Clonal Immumentioning

confidence: 60%

Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

Bortolomeazzi

Keddar

Montorsi

et al. 2020

Preprint

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Colorectal cancers (CRCs) show variable response to immune checkpoint blockade, which can only partially be explained by the variability of tumour mutational burden. To dissect the cellular and molecular determinants of response we performed a multi-omic screen of 721 cancer regions from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab. Multi-regional whole exome, RNA and T-cell receptor sequencing show that, within hypermutated CRCs, response to both anti-PD1 agents is not positively associated with tumour mutational burden but with high clonality of immunogenic mutations, expanded T cells, low activation of the WNT pathway and active immune escape mechanisms. Coupling high-dimensional imaging mass cytometry with multiplexed immunofluorescence and computational spatial analysis, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 cells interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting cytotoxic anti-tumour activity.

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“…To study this hypothesis, we first collated the largest publicly available cohort of ICItreated (anti-PD1/anti-PDL1) patient's responses with TMB and demographic information, comprising 1959 patients [4,5,7,8] together with an additional new cohort of 318 patients, comprising a total of 2277 patients across 14 cancer types. Analyzing this combined cohort, we first aimed to depict the association between TMB-H and patients' response to ICI in each cancer type.…”

Section: Mainmentioning

confidence: 99%

Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

Sinha

Valero

et al. 2021

Preprint

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The FDA has recently approved high tumor mutational burden (TMB), defined by ≥10 mutations/Mb, as a biomarker for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies testify that high TMB levels are only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may modulate the stratification power of TMB (termed TMB power) in a cancer type, leading to this observation. To systematically study this hypothesis, we analyzed TCGA expression data to infer the levels of 31 immune-related factors characteristic of the TME of different cancer types. We integrated this information with TMB and response data of 2,277 patients treated with anti-PD1 or anti-PD-L1 ICI to identify the key immune factors that can determine TMB power across 14 different cancer types. We find that high levels of M1 macrophages and low resting dendritic cells in the TME characterize cancer types with high TMB power. A model based on these two immune factors is strongly predictive of the TMB power in a given cancer type (Spearman Rho=0.76, P<3.6x10-04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. Our analysis indicates that TMB-High may be highly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.

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The association between tumor mutational burden and prognosis is dependent on treatment context

Cited by 185 publications

References 28 publications

Analyzing and Validating the Prognostic Value of a TNF-Related Signature in Kidney Renal Clear Cell Carcinoma

Analyzing and Validating the Prognostic Value of a TNF-Related Signature in Kidney Renal Clear Cell Carcinoma

Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

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