Local activation of p53 in the tumor microenvironment overcomes immune suppression and enhances antitumor immunity

Gang Guo, Miao Yu, Wei Xiao, Esteban Celis, Yan Cui

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mutations in tumor suppressor p53 remain a vital mechanism of tumor escape from apoptosis and senescence. Emerging evidence suggests that p53 dysfunction also fuels inflammation and supports tumor immune evasion, thereby serving as an immunological driver of tumorigenesis. Therefore, targeting p53 in the tumor microenvironment (TME) also represents an immunologically desirable strategy for reversing immunosuppression and enhancing antitumor immunity. Using a pharmacological p53 activator nutlin-3a, we show that local p53 activation in TME comprising overt tumor-infiltrating leukocytes (TILeus) induces systemic antitumor immunity and tumor regression, but not in TME with scarce TILeus, such as B16 melanoma. Maneuvers that recruit leukocytes to TME, such as TLR3 ligand in B16 tumors, greatly enhanced nutlin-induced antitumor immunity and tumor control. Mechanistically, nutlin-3a-induced antitumor immunity was contingent on two nonredundant but immunologically synergistic p53-dependent processes: reversal of immunosuppression in the TME and induction of tumor immunogenic cell death, leading to activation and expansion of polyfunctional CD8 CTLs and tumor regression. Our study demonstrates that unlike conventional tumoricidal therapies, which rely on effective p53 targeting in each tumor cell and often associate with systemic toxicity, this immune-based strategy requires only limited local p53 activation to alter the immune landscape of TME and subsequently amplify immune response to systemic antitumor immunity. Hence, targeting the p53 pathway in TME can be exploited to reverse immunosuppression and augment therapeutic benefits beyond tumoricidal effects to harness tumor-specific, durable, and systemic antitumor immunity with minimal toxicity.

Original languageEnglish (US)
Pages (from-to)2292-2305
Number of pages14
JournalCancer Research
Volume77
Issue number9
DOIs
StatePublished - May 1 2017

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Tumor Microenvironment
Immunity
Neoplasms
Immunosuppression
Tumor Escape
Leukocytes
Experimental Melanomas
Carcinogenesis
Cell Death
Pharmacology
Apoptosis
Ligands
Inflammation
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Local activation of p53 in the tumor microenvironment overcomes immune suppression and enhances antitumor immunity. / Guo, Gang; Yu, Miao; Xiao, Wei; Celis, Esteban; Cui, Yan.

In: Cancer Research, Vol. 77, No. 9, 01.05.2017, p. 2292-2305.

Research output: Contribution to journalArticle

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