Back to Search
Start Over
Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment.
- Source :
-
Cancer research [Cancer Res] 2021 Jun 01; Vol. 81 (11), pp. 3079-3091. Date of Electronic Publication: 2021 Jan 27. - Publication Year :
- 2021
-
Abstract
- p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103 <superscript>+</superscript> antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet <superscript>+</superscript> Eomes <superscript>+</superscript> CD8 <superscript>+</superscript> T cells and the CD8 <superscript>+</superscript> /Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo , which coincided with T-cell-mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, antitumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering antitumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors. SIGNIFICANCE: This study provides a mechanistic rationale for combining checkpoint blockade immunotherapy with MDM2 inhibitors in patients with wild-type p53 tumors.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis
Cell Proliferation
Colonic Neoplasms immunology
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Drug Therapy, Combination
Female
Humans
Imidazoles pharmacology
Immune Checkpoint Inhibitors pharmacology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Nude
Pyrimidines pharmacology
Pyrroles pharmacology
Stromal Cells drug effects
Tumor Cells, Cultured
Tumor Microenvironment drug effects
Xenograft Model Antitumor Assays
CD8-Positive T-Lymphocytes immunology
Colonic Neoplasms drug therapy
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Stromal Cells immunology
Tumor Microenvironment immunology
Tumor Suppressor Protein p53 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33504557
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-0189