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Low Mutation Burden in Ovarian Cancer May Limit the Utility of Neoantigen-Targeted Vaccines
Spencer D Martin1,2,3, Scott D Brown3, Darin A Wick1
1Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, Canada.
Abstract:
Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens.
Insights
Neoantigen vaccines show promise but may not be effective for low-mutation cancers like ovarian cancer. This study found limited success in a mouse model, suggesting broader applicability challenges for neoantigen-targeted therapies.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Advances in sequencing enable neoantigen identification for cancer immunotherapy.
- Neoantigen-targeted vaccines show promise but have mainly been studied in high-mutation cancers.
- The efficacy of neoantigen vaccines in low-to-intermediate mutation burden cancers, like ovarian cancer, remains uncertain.
Purpose of the Study:
- To evaluate the potential of neoantigen-targeted vaccines in a murine ovarian cancer model (ID8-G7).
- To determine if neoantigen vaccines can elicit anti-tumor immune responses and improve survival in ovarian cancer.
- To assess the prevalence of authentic neoantigens in human ovarian cancers compared to lung cancers.
Main Methods:
- Whole exome and transcriptome sequencing of ID8-G7 cells to identify somatic mutations.
- Prediction and synthesis of MHC class I binding peptides from missense mutations.
- Immunization of mice with synthetic long peptide vaccines and assessment of T cell responses and survival.
- In vitro validation of neoantigen recognition by T cells.
- Bioinformatic analysis of The Cancer Genome Atlas (TCGA) data for neoantigen prevalence in ovarian and lung cancers.
Main Results:
- Identified 92 somatic mutations, with 39 transcribed missense mutations in ID8-G7 cells.
- Seven out of 17 tested neoantigen vaccines induced mutation-specific CD4/CD8 T cell responses in mice.
- No significant improvement in survival was observed in either prophylactic or therapeutic settings.
- Neoantigen-specific T cells did not recognize ID8-G7 tumor cells in vitro, suggesting lack of presentation.
- Analysis of TCGA data indicated a lower likelihood of authentic neoantigens in high-grade serous ovarian cancer (12%) compared to lung cancer (51%).
Conclusions:
- Neoantigen-targeted vaccines may have limited efficacy in cancers with intermediate to low mutation burdens, such as ovarian cancer.
- The lack of tumor recognition by vaccine-induced T cells highlights challenges in identifying and targeting truly presented neoantigens.
- Findings suggest that the applicability of neoantigen vaccines may be restricted to specific cancer types with higher mutation rates.
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