Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Ziad Bakouny,Bradley A Mcgregor,Meng Xiao He,Xiao X Wei,David A Braun,Amin H Nassar,Miriam Sant’Angelo,Sylvan C Baca,Jackson Nyman,Natalie I Vokes ,Pier Vitale Nuzzo,Sarah Abou Alaiwi,Sabrina Y Camp ,Catherine J Wu,Alice Bosma-Moody,Kevin Bi,Michelle S Hirsch,Michael B Atkins,Mark Pomerantz,Maura Sticco-Ivins,Steven L Chang,David F Mcdermott,Xīn Gào ,Eliezer M Van Allen,Leigh Ellis,Jacob E Berchuck,Shaan Dudani,Miriam Ficial,Jihye Park,Gwo Shu Mary Lee ,Ronan Flippot,Abdallah Flaifel,Thai H Ho,Wanling Xie,Laure Hirsch,Srinivas R Viswanathan,Wenting Pan,Stephen Tang,W Marston Linehan,Lauren C Harshman,Matthew L Freedman,Petra Ross‐Macdonald ,Giannicola Genovese,Maxine Sun,John A Steinharter,Sachet A Shukla,Yue Hou,Megan Wind‐Rotolo ,Juliet Forman,Gabrielle Bouchard,Sabina Signoretti,Daniel Y.c Heng ,Toni K Choueiri

doi:10.1038/s41467-021-21068-9

Abstract

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Highlights

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization
Extending from the Hallmark GSEA analysis, 243 genes had significantly increased expression in S/R compared to non-S/R RCC independently across the two cohorts, including multiple cell cycle and proliferation (CCNB1, CDC45, CDC6, CDCA3, CDCA7, CDCA8, CDK6, and MKI67), immune (HIVEP3, IFI16, IFI35, IL15RA, and LAG3), and metastasis-implicated[22] (ACTB, ANLN, ARPC1B, ARPC5, and ARPC5L, CD44) genes as well as chemokine (CXCL9) and antigen presenting machinery (TAP1, TAP2, CALR, PSMA5, PSMB10, PSMB4, PSMC2, PSME2) genes that may be driving the immune infiltration in these tumors
In accordance with our other analyses, we found the eTME signatures tended to be enriched in S/R compared to non-S/R RCC

Summary

Introduction

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Sarcomatoid and rhabdoid features represent forms of dedifferentiation of RCC tumors and can occur in the same tumor or independently of each other[3] These features can develop over any background RCC histology, including clear cell, papillary, and chromophobe RCC. To define the molecular properties underlying the S/R clinical subtype and determine their relationship to potentially enhanced response to ICI, we perform an expanded clinical and molecular integrated characterization of S/R RCC in both clinical trial and real-world cohorts, assessing clinical outcomes on ICI, genomic and RNA sequencing (RNA-seq), immunohistochemical (IHC) staining for PD-L1, immunofluorescence (IF)-based assessment of immune infiltration, and transcriptomic evaluation of sarcomatoid cell lines (Fig. 1a)

Methods

Results

Conclusion