POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Endometrial cancers with POLE mutations (polymerase proofreading exonuclease domain) represent 7-12% of cases.
• These ultramutated tumors exhibit an excellent clinical prognosis.
• The link between mutation burden, immune response, and cancer outcomes is an area of active research.

Purpose of the Study:

• To investigate the immunogenicity of POLE-mutant endometrial cancers.
• To determine if increased mutation burden in POLE-mutant tumors correlates with enhanced immune response.
• To explore the potential mechanism behind the favorable prognosis of these cancers.

Main Methods:

• Analysis of immune cell infiltration and activation in 47 POLE-mutant endometrial tumors.
• Confirmation using RNA sequencing data from The Cancer Genome Atlas (TCGA) endometrial cancer series.
• In silico prediction of neoepitope load in POLE-mutant versus other endometrial cancers.

Main Results:

• POLE-mutant endometrial cancers demonstrated an enhanced cytotoxic T-cell response.
• Increased CD8(+) tumor-infiltrating lymphocytes and CD8A expression were observed.
• Upregulation of T-cell effector markers (T-bet, Eomes, IFNG, PRF, granzyme B) and exhaustion markers indicated chronic antigen exposure.

Conclusions:

• Ultramutated POLE-mutant endometrial cancers exhibit a robust intratumoral T-cell response.
• This immune response is likely driven by an enrichment of antigenic neopeptides.
• The findings suggest a plausible mechanism for the excellent prognosis associated with POLE mutations.