Pharmacologic Activation of p53 Triggers Viral Mimicry Response Thereby Abolishing Tumor Immune Evasion and Promoting Antitumor Immunity

Abstract

The repression of repetitive elements is an important facet of p53's function as a guardian of the genome. Paradoxically, we found that p53 activated by MDM2 inhibitors induced the expression of endogenous retroviruses (ERVs) via increased occupancy on ERV promoters and inhibition of two major ERV repressors, histone demethylase LSD1 and DNA methyltransferase DNMT1. Double-stranded RNA stress caused by ERVs triggered type I/III interferons expression and antigen processing and presentation. Pharmacological activation of p53 in vivo unleashed the interferon program, promoted T cell infiltration and significantly enhanced the efficacy of checkpoint therapy in a xenograft tumor model. Furthermore, MDM2 inhibitor ALRN-6924 induced a viral mimicry pathway and tumor inflammation signature genes in melanoma patients.Our results identify ERV expression as the central mechanism whereby p53 induction overcomes tumor immune evasion and transforms tumor microenvironment to a favorable phenotype, providing a rationale for the synergy of MDM2 inhibitors and immunotherapy. Significance:We found that p53 activated by MDM2 inhibitors induced the expression of ERVs, in part due via epigenetic factors LSD1 and DNMT1. Induction of IFN response caused by ERV de-repression upon p53-targeting therapies provides a possibility to overcome resistance to immune checkpoint blockade and potentially transform 'cold' tumors into 'hot'.

Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification

“…Tumours immunologically classified as intermediate showed enrichment of TP53 mutations and losses in genes related to antigen presentation and interferon signalling. Interestingly, loss of TP53 in cancer cells promotes the recruitment of immune suppressive cells and attenuates the response of both cytotoxic and T-helper cells 43 44. Therefore, the increased rate of TP53 mutations seen in the intermediate class could be key in promoting an immunosuppressive microenvironment.…”

Distinct molecular phenotype and the potential prognostic value of immune prognostic index and tumor infiltrating lymphocytes in hepatoid adenocarcinoma of stomach

“…GC patients with wild type TP53 generally have plentiful intratumoral lymphocyte infiltration [28] , which is associated with favorable prognosis and increased ICIs sensitivity. Recently, an in vivo study further corroborated that the TP53 is a favorable condition for T cell infiltration and checkpoint therapy [29] . Likewise, the present study also observed an improved survival trend in patients with wild-type TP53 status, and the potential high mutation rate and TILs in MSS/TP53+ might be the underlying mechanisms for improved survival and further suggest the rationality of ICIs therapy in appropriated HAS patients.…”

Discovering the Triad between Nav1.5, Breast Cancer, and the Immune System: A Fundamental Review and Future Perspectives

“…Thus, it can be said that the presence of migrating metastatic cancer cells may stimulate immune response within the human body [ 95 , 96 , 97 ]. The biomarkers present on these migrating cancer cells can be recognised by the immune cells and eventually trigger the immune system to produce antibodies to neutralise the expression of the biomarkers [ 95 , 98 ]. The crosstalk between cancer and immune cells contributes to another layer of complexity to our understanding of the formation of metastasis, but at the same time opens new therapeutic opportunities for patients such as cancer immunotherapy [ 96 , 99 ].…”