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Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment.
Wang, Hui Qin; Mulford, Iain J; Sharp, Fiona; Liang, Jinsheng; Kurtulus, Sema; Trabucco, Gina; Quinn, David S; Longmire, Tyler A; Patel, Nidhi; Patil, Roshani; Shirley, Matthew D; Chen, Yan; Wang, Hao; Ruddy, David A; Fabre, Claire; Williams, Juliet A; Hammerman, Peter S; Mataraza, Jennifer; Platzer, Barbara; Halilovic, Ensar.
Afiliação
  • Wang HQ; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Mulford IJ; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Sharp F; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Liang J; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Kurtulus S; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Trabucco G; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Quinn DS; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Longmire TA; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Patel N; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Patil R; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Shirley MD; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Chen Y; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Wang H; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Ruddy DA; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Fabre C; Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Williams JA; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Hammerman PS; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Mataraza J; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Platzer B; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Halilovic E; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts. ensar.halilovic@novartis.com.
Cancer Res ; 81(11): 3079-3091, 2021 06 01.
Article em En | MEDLINE | ID: mdl-33504557
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+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8+/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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Proteína Supressora de Tumor p53 / Células Estromais / Neoplasias do Colo / Linfócitos T CD8-Positivos / Proteínas Proto-Oncogênicas c-mdm2 / Microambiente Tumoral Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Proteína Supressora de Tumor p53 / Células Estromais / Neoplasias do Colo / Linfócitos T CD8-Positivos / Proteínas Proto-Oncogênicas c-mdm2 / Microambiente Tumoral Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2021 Tipo de documento: Article