Xiaolei Zhou1, Gema Sanz Santos1, Yue Zhan1,2, Mariana M S Oliveira1, Shiva Rezaei1, Madhurendra Singh1, Sylvain Peuget1, Lisa S Westerberg1, John Inge Johnsen3, Galina Selivanova4,5. 1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65, Stockholm, Sweden. 2. Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China. 3. Department of Women's and Children's Health, Childhood Cancer Research Unit, Karolinska Institutet, 171 77, Stockholm, Sweden. 4. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65, Stockholm, Sweden. galina.selivanova@ki.se. 5. Department of Microbiology, Tumor and Cell Biology, Biomedicum C8, Karolinska Institutet, 171 65, Stockholm, Sweden. galina.selivanova@ki.se.
Abstract
BACKGROUND: p53 mutants contribute to the chronic inflammatory tumour microenvironment (TME). In this study, we address the mechanism of how p53 mutants lead to chronic inflammation in tumours and how to transform it to restore cancer immune surveillance. METHODS: Our analysis of RNA-seq data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project revealed that mutant p53 (mtp53) cancers correlated with chronic inflammation. We used cell-based assays and a mouse model to discover a novel gain of function of mtp53 and the effect of the mtp53 reactivating compound APR-246 on the anti-tumour immune response. RESULTS: We found that tumour samples from patients with breast carcinoma carrying mtp53 showed elevated Interferon (IFN) signalling, Tumour Inflammation Signature (TIS) score and infiltration of CD8+ T cells compared to wild type p53 (wtp53) tumours. We showed that the expression of IFN and immune checkpoints were elevated in tumour cells in a mtp53-dependent manner, suggesting a novel gain of function. Restoration of wt function to mtp53 by APR-246 induced the expression of endogenous retroviruses, IFN signalling and repressed immune checkpoints. Moreover, APR-246 promoted CD4+ T cells infiltration and IFN signalling and prevented CD8+ T cells exhaustion within the TME in vivo. CONCLUSIONS: Breast carcinomas with mtp53 displayed enhanced inflammation. APR-246 boosted the interferon response or represses immune checkpoints in p53 mutant tumour cells, and restores cancer immune surveillance in vivo.
BACKGROUND: p53 mutants contribute to the chronic inflammatory tumour microenvironment (TME). In this study, we address the mechanism of how p53 mutants lead to chronic inflammation in tumours and how to transform it to restore cancer immune surveillance. METHODS: Our analysis of RNA-seq data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project revealed that mutant p53 (mtp53) cancers correlated with chronic inflammation. We used cell-based assays and a mouse model to discover a novel gain of function of mtp53 and the effect of the mtp53 reactivating compound APR-246 on the anti-tumour immune response. RESULTS: We found that tumour samples from patients with breast carcinoma carrying mtp53 showed elevated Interferon (IFN) signalling, Tumour Inflammation Signature (TIS) score and infiltration of CD8+ T cells compared to wild type p53 (wtp53) tumours. We showed that the expression of IFN and immune checkpoints were elevated in tumour cells in a mtp53-dependent manner, suggesting a novel gain of function. Restoration of wt function to mtp53 by APR-246 induced the expression of endogenous retroviruses, IFN signalling and repressed immune checkpoints. Moreover, APR-246 promoted CD4+ T cells infiltration and IFN signalling and prevented CD8+ T cells exhaustion within the TME in vivo. CONCLUSIONS: Breast carcinomas with mtp53 displayed enhanced inflammation. APR-246 boosted the interferon response or represses immune checkpoints in p53 mutant tumour cells, and restores cancer immune surveillance in vivo.
Authors: Monisankar Ghosh; Suchandrima Saha; Julie Bettke; Rachana Nagar; Alejandro Parrales; Tomoo Iwakuma; Adrianus W M van der Velden; Luis A Martinez Journal: Cancer Cell Date: 2021-02-04 Impact factor: 31.743
Authors: Eran Elinav; Roni Nowarski; Christoph A Thaiss; Bo Hu; Chengcheng Jin; Richard A Flavell Journal: Nat Rev Cancer Date: 2013-11 Impact factor: 69.800