Abstract B019: Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment
Authors: Alchoueiry Michel , Labaki Chris , Zhang Long , Hou Yue , Bi Kevin , Hobeika Charbel , Wells J. Connor , Takemura Kosuke , Bakouny Ziad , Camp Sabrina , Priolo Carmen , Khabibullin Damir , Schindler Nicholas , Saliby Renee Maria , Saad Eddy , Salem Samer , Daou Melissa , McKay Rana , Pal Sumanta , Heng Daniel , Van Allen Eliezer , Shukla Sachet , Choueiri Toni , Braun David , Henske Elizabeth 
Published: August 2023

Abstract
Background: Chromophobe renal cell carcinoma (ChRCC) represents 5% of all kidney cancers. In contrast to clear cell RCC (ccRCC), the immune landscape of ChRCC and its response to immunotherapy remain poorly characterized. We sought to evaluate the clinical outcomes of patients with ChRCC treated with immuno-oncology (IO)-based regimens, and assess the immune cell composition, phenotypic state, and T cell specificity in the tumor microenvironment of ChRCC. Methods: Using real-world data from the International Metastatic RCC Database Consortium, we analyzed the survival outcomes and objective responses of patients with advanced ChRCC to currently adopted IO-based regimens (i.e. dual IO therapy or IO + vascular endothelial growth factor targeted therapy [VEGF-TT]) in the first-line setting, as compared to patients with ccRCC. Single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq) were performed on ChRCC and related oncocytic neoplasms (i.e. renal oncocytoma [RO] and low-grade oncocytic tumor [LOT]) samples with matched normal kidney specimens. The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Results: Compared to patients with ccRCC (n=856) treated with first-line IO-based regimens, patients with ChRCC (n=31) had a lower overall survival (median: 24.7 vs. 50.5 months, p&lt;0.001) and lower time to treatment failure (median: 4.5 vs. 11.0 months, p&lt;0.001). Similarly, patients with ChRCC had a significantly lower overall response rate than those with ccRCC (12.0 vs. 47.1%, respectively; p&lt;0.001). When evaluating immune cell infiltration, renal oncocytic tumors (ChRCC, RO, and LOT) exhibited a low density of CD45+ cells (mean: 739 ± 114 cells/mm2; n=5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm2; n=5) (p&lt;0.05). Single-cell analysis was performed on 46,817 cells from 5 tumors (ChRCC: n=3, RO: n=1 and LOT: n=1) and 4 samples from adjacent normal kidney. Across all tumors, CD8+ T cell clusters displayed a lower expression of immune checkpoints (i.e. PDCD1, CTLA4, LAG3, HAVCR2, and TIGIT) as compared to CD8+ T-cells from ccRCC. This was further validated in the analysis of bulk RNA-seq data from the TCGA, with a significantly lower expression of all immune checkpoints in ChRCC compared to both ccRCC (p&lt;0.01) and papillary RCC (pRCC; p&lt;0.01). Analysis of the T cell receptor repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not show any pattern of clonal expansion, and a higher proportion of T cells in ChRCC were inferred to have a viral specificity, compared to ccRCC (0.79 vs. 0.1%, respectively). Conclusions: Patients with metastatic ChRCC appear to display poor clinical outcomes when treated with IO-based regimens, compared to ccRCC. Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, and a non-exhausted immune phenotype.
Citation Format: Michel Alchoueiry, Chris Labaki, Long Zhang, Yue Hou, Kevin Bi, Charbel Hobeika, J. Connor Wells, Kosuke Takemura, Ziad Bakouny, Sabrina Camp, Carmen Priolo, Damir Khabibullin, Nicholas Schindler, Renee Maria Saliby, Eddy Saad, Samer Salem, Melissa Daou, Rana McKay, Sumanta Pal, Daniel Heng, Eliezer Van Allen, Sachet Shukla, Toni Choueiri, David Braun, Elizabeth Henske. Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B019.