TP53 mutations predict poor response to immunotherapy in patients with metastatic solid tumors

Area of Science:

• Oncology
• Cancer Genomics
• Immunotherapy

Background:

• The TP53 gene is frequently mutated in various cancers.
• The R175H mutation in TP53 is a structural alteration affecting the p53 protein's DNA binding domain.
• Understanding the impact of specific TP53 mutations on immunotherapy response is crucial.

Purpose of the Study:

• To investigate why the TP53 R175H mutation worsens immunotherapy response.
• To analyze the tumor immune microenvironment in relation to TP53 R175H.
• To examine the expression of immune cells and PD-1 in tumors with TP53 R175H.

Main Methods:

• Analysis of tumor samples from 1770 metastatic cancer patients.
• Utilized TruSight™ Oncology 500 assay (TSO 500) for genetic analysis.
• RNA sequencing was performed to assess immune response pathways and gene expression.

Main Results:

• TP53 mutations were found in 57.2% of patients; R175H was the most common (7.5%).
• TP53 R175H mutations were associated with significantly worse overall survival after chemotherapy and immunotherapy.
• RNA sequencing revealed downregulated immune response pathways and reduced CD8(+) T cell PD-1 expression in R175H tumors.

Conclusions:

• Different TP53 mutations have varying prognoses in metastatic cancer patients treated with chemotherapy or immunotherapy.
• TP53 mutations, particularly R175H, appear to downregulate the anti-tumor immune response.
• Further functional and prospective studies are needed to validate these findings and develop better prognostic markers.