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PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon
Benoit Rousseau1, Ivan Bieche2,3, Eric Pasmant3,4
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti-PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.
Significance:
POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti-PD-1 efficacy in mismatch repair-proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 1397.
Insights
Specific polymerase epsilon (POLE) proofreading defects sensitize tumors to immunotherapy. Tumors with POLE proofreading deficiency show high response rates to PD-1 blockade therapy, identifying a novel biomarker.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Missense mutations in the polymerase epsilon (POLE) gene can cause proofreading defects, leading to increased tumor mutation rates.
- These POLE mutations have been linked to enhanced sensitivity to checkpoint blockade immunotherapy, but response rates vary.
- Many POLE-mutated tumors do not benefit from current immunotherapy treatments.
Purpose of the Study:
- To investigate the efficacy of nivolumab in patients with advanced mismatch repair-proficient POLE-mutated solid tumors.
- To identify specific POLE mutation variants associated with immunotherapy response.
- To determine if POLE proofreading deficiency can serve as a biomarker for anti-PD-1 therapy.
Main Methods:
- Prospective multicenter clinical trial assessing nivolumab efficacy.
- Analysis of patients with advanced mismatch repair-proficient POLE-mutated solid tumors.
- Correlation of specific POLE mutation types with tumor mutational burden, T-cell infiltrates, and response to anti-PD-1 monotherapy.
Main Results:
- Only POLE pathogenic mutations in the exonuclease domain's DNA binding or catalytic sites led to high mutational burden and specific mutational signatures.
- These specific POLE mutations were associated with high T-cell infiltrates and a high response rate to anti-PD-1 monotherapy.
- POLE mutations not affecting proofreading did not benefit from PD-1 blockade.
Conclusions:
- Specific DNA repair defects, like POLE proofreading deficiency, can sensitize tumors to immunotherapy.
- POLE proofreading deficiency is a novel, tissue-agnostic biomarker for predicting response to PD-1 checkpoint blockade therapy.
- This finding highlights the importance of specific genetic alterations in guiding cancer treatment decisions.
