Abstract 2807: Immune cell-dependent resistance to LAG3 blockade in SMARCB1-deficient renal medullary carcinoma

Abstract Background: Renal medullary carcinoma (RMC) is an exceptionally aggressive kidney cancer of young individuals with sickle cell trait, characterized by SMARCB1 loss, rapid progression, and a median survival of ∼13 months. Transcriptomic profiling shows a highly inflamed microenvironment with broad immune-checkpoint upregulation. Among these, PD-1 (log2 fold-change 1.7; FDR = 0.008) is increased, and LAG-3 (log2 fold-change 4.6; FDR < 0.0001) shows one of the strongest elevations relative to adjacent kidney tissue. These findings motivated an RMC-specific clinical trial testing anti-PD-1 plus high-dose anti-LAG-3 (NCT05347212), yet mechanisms underlying resistance to LAG-3 blockade remain unknown. Study Design and Methods: To investigate RMC response to PD-1 and LAG-3 inhibition, we used a somatic-mosaic immunocompetent genetically engineered mouse model (GEMM) of RMC on a sickle-trait background. We compared anti-PD-1 and anti-LAG-3 monotherapy with isotype IgG in immunocompetent mice to assess baseline sensitivity to checkpoint inhibition. To dissect mechanisms of LAG-3 resistance, we evaluated anti-LAG-3 treatment in RAG1-knockout mice lacking mature B and T cells and examined anti-LAG-3 under CD4+ T-cell depletion to identify the immune subsets driving resistance. Tumor weights were assessed at endpoint, and statistical comparisons were performed using the Mann-Whitney test. Results: Anti-PD-1 monotherapy failed to control tumor growth, confirming intrinsic resistance to PD-1 blockade (mean tumor weight: IgG 0.58 g vs anti-PD-1 0.75 g; p = 0.6682). In contrast, anti-LAG-3 monotherapy exacerbated tumor progression (IgG 0.74 g vs anti-LAG-3 1.27 g; p = 0.0297). Loss of adaptive immunity partially reversed this phenotype: in RAG1-knockout mice, anti-LAG-3 showed a trend toward reduced tumor burden (IgG 1.415 g vs anti-LAG-3 0.61 g; p = 0.127). CD4+ T-cell depletion abrogated resistance, yielding significantly lower tumor weights under anti-LAG-3 (anti-LAG-3 1.39 g vs anti-LAG-3 + CD4 depletion 0.75 g; p = 0.0291). Conclusions: Our findings identify an immune cell-dependent mechanism limiting the efficacy of LAG-3 blockade in SMARCB1-deficient RMC. Disrupting this axis, alone or alongside PD-1/LAG-3 inhibition, emerges as a testable strategy to blunt immune checkpoint therapy-induced adaptive reprogramming and restore anti-tumor activity. Citation Format: Jing Qian, Kai Yu, Deepa Bisht, Melinda Soeung, Pankaj Chauhan, Fei Duan, Menuka Karki, Rong He, Nizar M. Tanir, Hania Khan, Zilong Zhao, Luigi Perelli, Giannicola Genovese, Linghua Wang, Jianjun Gao, Pavlos Msaouel. Immune cell-dependent resistance to LAG3 blockade in SMARCB1-deficient renal medullary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2807.