Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

Braun, David A.; Street, Kelly; Burke, Kelly P.; Cookmeyer, David L.; Denize, Thomas; Pedersen, Christina Bligaard; Gohil, Satyen; Schindler, Nicholas; Pomerance, Lucas; Hirsch, Laure; Bakouny, Ziad; Hou, Yue; Forman, Juliet; Huang, Teddy; Li, Shuqiang; Cui, Ang; Keskin, Derin B.; Steinharter, John A.; Bouchard, Gabrielle; Sun, Maxine; Pimenta, Erica Maria; Xu, Wenxin; Mahoney, Kathleen M.; McGregor, Bradley A.; Hirsch, Michelle S.; Chang, Steven L.; Livak, Kenneth J.; McDermott, David F.; Shukla, Sachet A.; Olsen, Lars Rønn; Signoretti, Sabina; Sharpe, Arlene H.; Irizarry, Rafael A.; Choueiri, Toni K.; Wu, Catherine J.

doi:10.1016/j.ccell.2021.02.013

Cited by 285 publications

(380 citation statements)

References 88 publications

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“…Nonetheless, bulk RNA-seq is limited by unknown cell-type admixture, so future work should focus on large cohorts of paired ICB-naive and ICB-resistant biopsies using single-cell approaches. Multiplex imaging analyses may elucidate mechanisms of cross talk, which appear pervasive in RCC ( Braun et al., 2021 ). This is particularly pressing given the upregulation of immunosuppressive genes in both TAMs and cancer cells, which may ultimately precipitate resistance.…”

Section: Discussionmentioning

confidence: 99%

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

et al. 2021

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“…For the "bulk RMC signature", the upregulated genes from the differential analysis of the MDACC RMC cohort (11 tumours versus 6 NAT) were selected using log2FC > 2 and FDR < 0.01 (Msaouel et al, 2020a). The TAM "M1/M2" signatures were adapted from (Braun et al, 2021). The CAF "iCAF/myCAF" signatures" were adapted from (Elyada et al, 2019).…”

Section: Functional Analysis Using Scrna-seq Datamentioning

confidence: 99%

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities

Davidson

Helleux

et al. 2021

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Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities.

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“…Furthermore, this evenness metric could be extended to other solid tumor types as a quantitative metric of host contributions to immune infiltration as a possible result of tumor evolution. Such characterizations might become especially interesting in the context of terminally exhausted CD8+ T cells, which were recently shown to be enriched in advanced renal cell carcinoma, interacting with M2-like tumor-associated macrophages leading to immune dysfunction and poorer prognosis ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma

Ferrall‐Fairbanks

Chakiryan

et al. 2021

Preprint

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Immune-modulating systemic therapies are often used to treat metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor-immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we used complementarity determining region-3 (CDR3) sequence recovery counts of the tumor infiltrating lymphocytes, and quantified tumor infiltration by sequences recovered from patient tumors by applying a generalized diversity index (GDI) to CDR3 sequence distributions across two distinct ccRCC cohorts. GDI can be understood as a curve over a continuum of diversity scales and allows sensitive characterization of distributions to capture richness, evenness, and subsampling uncertainty, along with other important metrics. For example, richness quantifies the total unique sequence count, while evenness quantifies similarities across sequence frequencies. We observed significant differences in receptor sequence diversity across gender and race. Further, our analysis revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. We identified a novel and robust measure of distribution evenness, using GDI's inflection point (IP). High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. Our results propose a new quantitative tool that can be used to better characterize patient-level differences related to immune cell infiltration and, can be used to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.

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Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

Cited by 285 publications

References 88 publications

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities

Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma

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