Abstract 2702: Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab
Authors: Soeung Melinda , Yan Xinmiao , Zhang Li , Perelli Luigi , Chen Jianfeng , Tidwell Becky Slack , Khan Hania , Le Courtney N. , Lam Truong N. , Bhattacharya Nirjar , Shah Rutvi , Ho I-Lin , Chen Ziheng , Lundgren Sebastian R. , Feng Ningping , Zanca Ciro , Karki Menuka , Millward Niki Marie Zacharias , He Rong , Sheth Rahul A. , Tharakeswara Bathala K. , Rao Priya , Daw Najat C. , Tripathi Durga N. , Walker Cheryl L. , Han Guangchun , Chu Yanshuo , Wang Ruiping , Dang Minghao , Dai Enyu , Peng Fuduan , Liu Yunhe , Jadhav Akshaya S. , Lang Wenhua , Arrechedera Claudio A. , Clemente Leticia Campos , Parra-Cuentas Edwin R. , Lu Hsinyi , Haymaker Cara , Wistuba Ignacio I. , Futreal Andrew , Heffernan Timothy , Viale Andrea , Draetta Giulio F. , Tannir Nizar M. , Gao Jianjun , Wang Linghua , Genovese Giannicola , Msaouel Pavlos 
Published: March 2024

Abstract
Renal medullary carcinoma (RMC) is a rare but highly aggressive SMARCB1-deficient kidney cancer that mainly afflicts young individuals of African descent and has few treatment options. Despite the advancements in immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. The majority of RMC patients treated with ICT have experienced aggressively progressive disease as the best response. This hyperprogression was confirmed in our prospective clinical trial of nivolumab plus ipilimumab specifically designed for RMC patients (ClinicalTrials.gov identifier: NCT03274258). To elucidate the mechanisms of resistance to ICT in RMC, we generated high-quality single-cell RNA sequencing data on 23,880 cells from 7 patients at baseline and 2 patients exhibiting hyperprogression after ICT intervention. Our analysis revealed that RMC tumor cells undergo a distinct transcriptional reconfiguration following ICT therapy. This reconfiguration is manifested by upregulation of S100A9 and activation of the MEK/ERK pathway, indicating that RMC tumor cells adopt myeloid-affiliated transcriptional circuits, potentially promoting cell proliferation and leading to hyperprogression. Using a mouse model of RMC, we further demonstrated in a controlled setting that ICT causes hyperprogressive disease via activation of MEK/ERK pathway and an increase of S100A9 positive tumor cells. This process can be reversed by inhibiting master regulators of this “myeloid mimicry” mechanism, such as the CEBPB/p300 complex in our mouse model of RMC, thus restoring sensitivity to ICT. These findings provide novel insights into RMC resistance to ICT and suggest valuable directions for the development of therapeutic strategies.
Citation Format: Melinda Soeung, Xinmiao Yan, Li Zhang, Luigi Perelli, Jianfeng Chen, Becky Slack Tidwell, Hania Khan, Courtney N. Le, Truong N. Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Ziheng Chen, Sebastian R. Lundgren, Ningping Feng, Ciro Zanca, Menuka Karki, Niki Marie Zacharias Millward, Rong He, Rahul A. Sheth, Bathala K. Tharakeswara, Priya Rao, Najat C. Daw, Durga N. Tripathi, Cheryl L. Walker, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya S. Jadhav, Wenhua Lang, Claudio A. Arrechedera, Leticia Campos Clemente, Edwin R. Parra-Cuentas, Hsinyi Lu, Cara Haymaker, Ignacio I. Wistuba, Andrew Futreal, Timothy Heffernan, Andrea Viale, Giulio F. Draetta, Nizar M. Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel. Hyperprogression due to myeloid mimicry in renal medullary carcinoma treated with nivolumab plus ipilimumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2702.