Abstract 945: PBRM1 loss reduces IFNγ-STAT1 activity and promotes resistance to immunotherapy and antiangiogenic therapy in renal cell carcinoma

Autor: Xian De Liu, Lijun Zhou, Anh Hoang, Truong Nguyen Anh Lam, Christine B. Peterson, Margie M. Moczygemba, Eric Jonasch, Haifeng Zhu, Xuesong Zhang, Wen Kong, Sevinj Isgandrova, Patrick G. Pilie
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research. 79:945-945
ISSN: 1538-7445
0008-5472
Popis: PBRM1 is a subunit of SWI/SNF complex that regulates chromatin accessibility for transcription factors, and more than 30% of clear cell renal cell carcinoma (RCC) contain PBRM1 mutations. Nivolumab (anti-PD-1) showed profound and prolonged response only in a subset of patients with advanced RCC. The impact of PBRM1 loss on response to immunotherapy in RCC patients still remains contradictory. It is important to develop immune competent murine RCC models that can precisely isolate the influence of PBRM1 loss on the tumor microenvironment. IFNγ-related gene expression profiles have been reported to predict response to anti-PD-1 blockade. We analyzed the effect of PBRM1 on the IFNγ STAT1 signaling pathway in isogenic murine RCC Renca cells. We observed that Pbrm1 knockout reduced IFNγ-induced STAT1 phosphorylation, and consequently the expression of downstream genes including Irf1, Cxc9 and Stat1 itself. Considering the critical role of CXCL9 in T cell recruitment, we found that Pbrm1 deficiency reduced accessibility to the Cxcl9 promoter by STAT1 and BRG1, the ATP-dependent enzyme subunit of the SWI/SNF complex. Furthermore, a bioinformatics analysis of the Cancer Genome Atlas of human RCC and our murine RCC RNAseq database showed that PBRM1inactivation was associated with reduced expression of an IFNγ-related mRNA profile, including checkpoint genes CTLA4 and PDCD1. These results revealed that PBRM1 loss reduced IFNγ signaling pathway activation and chromatin accessibility by the transcription factor STAT1. Since Pbrm1 deficiency reduced IFNγ-STAT1 activity and consequently Cxcl9 expression, we then compared the immune cell infiltration in both Pbrm1 proficient and deficient Renca tumors in BalB/C mice. As expected, Pbrm1 deficient tumors harbored fewer infiltrating CD3+ and CD8+ T cells, and expressed less PD-1. It has previously been reported that response to immune checkpoint therapy requires pre-existing T cells, and their intrinsic anti-tumor activity potentiated by blocking immune checkpoints. We found that Pbrm1 deficient tumors demonstrated longer latency but more resistance to immunotherapy with PD-1 blockade. We previously showed that antiangiogenic therapy increased T cell infiltration associated with PD-L1 upregulation, and proposed that antiangiogenic agents could promote the response to checkpoint blockade. Here we confirmed that antiangiogenic agent axitinib reduced Pbrm1 proficient tumor growth, and its combination with anti-PD-1 blockade exhibited synergistic efficacy. In contrast, neither axitinib monotherapy nor combination therapy with PD-L1 antibody exerted obvious control on Pbrm1 deficient tumor, indicating patients with PBRM1 functional mutation were more resistant to immunotherapy and antiangiogenic therapy. This study provides mechanistic insights into therapeutic response of PBRM1 mutated RCC. Citation Format: Xiande Liu, Wen Kong, Christine Peterson, Anh Hoang, Xuesong Zhang, Lijun Zhou, Patrick Pilie, Truong Lam, Haifeng Zhu, Sevinj Isgandrova, Margie Moczygemba, Eric Jonasch. PBRM1 loss reduces IFNγ-STAT1 activity and promotes resistance to immunotherapy and antiangiogenic therapy in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 945.
Databáze: OpenAIRE
Externí odkaz: