Abstract 646: Unravelling the mechanisms of resistance and hyperprogression of renal medullary carcinoma to immune checkpoint therapy
Authors: Jing Qian, Melinda Soeung, Xinmiao Yan, Kai Yu, Ciro Zanca, Li Zhang, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca Slack Tidwell, Hania Khan, Fei Duan, Menuka Karki, Rong He, Courtney N. Le, Truong N.A. Lam, Nirjar Bhattacharya, Mariah N. Williams, David H. Peng, Rutvi Shah, I-Lin Ho, Ningping Feng, Niki Millward Zacharias, Rahul Anil Sheth, Tharakeswara K. Bathala, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Hsinyi Lu, Cara L. Haymaker, Ignacio I. Wistuba, Andrew Futreal, Andrea Viale, Timothy Heffernan, Giulio F. Draetta, Nazir M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel
Journal: Cancer Research (2025)

Abstract Renal medullary carcinoma (RMC) is defined by the loss of the SMARCB1 tumor suppressor and represents one of the most aggressive kidney cancers, predominantly affecting young individuals of African descent with the sickle cell trait. RMC exhibits rapid progression, and poor response to standard therapies, with a median survival of only 13 months following diagnosis. In pursuit of more effective treatments, we launched two clinical trials specifically for patients with RMC evaluating anti-PD1 + anti-CTLA4 immune checkpoint therapy (ICT) with nivolumab + ipilimumab (ClinicalTrials.gov identifier: NCT03274258) and anti-PD1 + anti-LAG3 ICT using nivolumab + relatlimab (ClinicalTrials.gov identifier: NCT05347212). However, both trials were terminated early for futility due to resistance and hyperprogression by the established consensus Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 radiological criteria in Matos et al. Clin Cancer Res. 2020 (PMID: 31757877). Co-clinical experiments testing the same ICT regimens in our immunocompetent somatic mosaic genetically engineered mouse model (GEMM) of RMC demonstrated similar patterns of resistance and hyperprogression with ICT compared with IgG control. The combination of anti-PD1 with either anti-CTLA4 or anti-LAG3 significantly accelerated primary tumor progression and markedly increased metastatic burdens in the lung and liver of RMC mice. Comprehensive analyses, including longitudinally collected single-cell RNA sequencing from human RMC patient samples and RNA sequencing of GEMM RMC tumors revealed significant transcriptional reprogramming, enhanced tumor proliferation, activation of oncogenic pathways, and a shift toward myeloid-specific gene expression by RMC tumor cells in response to ICT. In our RMC mouse models, tumor cells have been engineered to express green fluorescent protein (GFP), enabling us to distinguish them from non-malignant mouse cells. Accordingly, multiplex immunofluorescence (mIF) revealed that tumor tissues from mice treated with ICT showed a significant increase of tumor cells co-expressing GFP and myeloid markers such as CD68, F4/80 and S100A9. Differential patterns of resistance and hyperprogression when RMC mice were treated with monotherapies targeting PD1, CTLA4, or LAG3. To counteract ICT-induced hyperprogression, we tested the CEBPB/p300 complex inhibitor IACS16898 which successfully induced tumor responses when combined with ICT in our RMC GEMM. IACS16898 treatment significantly reduced the expression of myeloid-associated markers on GFP+ tumor cells. Our study not only elucidates a novel mechanism of resistance and hyperprogression to PD1 plus either CTLA4 or LAG3 inhibition in SMARCB1-deficient cancers but also provides a foundation for targeting oncogenic and resistance pathways in RMC treated with distinct immunotherapy regimens. Citation Format: Jing Qian, Melinda Soeung, Xinmiao Yan, Kai Yu, Ciro Zanca, Li Zhang, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca Slack Tidwell, Hania Khan, Fei Duan, Menuka Karki, Rong He, Courtney N. Le, Truong N.A. Lam, Nirjar Bhattacharya, Mariah N. Williams, David H. Peng, Rutvi Shah, I-Lin Ho, Ningping Feng, Niki Millward Zacharias, Rahul Anil Sheth, Tharakeswara K. Bathala, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Hsinyi Lu, Cara L. Haymaker, Ignacio I. Wistuba, Andrew Futreal, Andrea Viale, Timothy Heffernan, Giulio F. Draetta, Nazir M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Unravelling the mechanisms of resistance and hyperprogression of renal medullary carcinoma to immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 646.