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The double-edged sword of cancer mutations: exploiting neoepitopes for the fight against cancer
Isabel Alvarado-Cruz1, Rithy Meas1, Sesha Lakshmi Arathi Paluri2
1Department of Therapeutic Radiology, Yale University, New Haven, CT, USA.
Abstract:
Defects in DNA repair have been linked to the accumulation of somatic mutations in tumours. These mutations can promote oncogenesis; however, recent developments have indicated that they may also lead to a targeted immune response against the tumour. This response is initiated by the development of new antigenic epitopes (neoepitopes) arising from mutations in protein-coding genes that are processed and then presented on the surface of tumour cells. These neoepitopes are unique to the tumour, thus enabling lymphocytes to launch an immune response against the cancer cells. Immunotherapies, such as checkpoint inhibitors (CPIs) and tumour-derived vaccines, have been shown to enhance the immunogenic response to cancers and have led to complete remission in some cancer patients. There are tumours that are not responsive to immunotherapy or conventional tumour therapeutics; therefore, there is a push for new treatments to combat these unresponsive cancers. Recently, combinatorial treatments have been developed to further utilise the immune system in the fight against cancer. These treatments have the potential to exploit the defects in DNA repair by inducing more DNA damage and mutations. This can potentially lead to the expression of high levels of neoepitopes on the surface of tumour cells that will stimulate an immunological response. Overall, exploiting DNA repair defects in tumours may provide an edge in this long fight against cancer.
Insights
Defects in DNA repair can cause mutations that trigger anti-cancer immune responses. Exploiting these defects with new therapies may improve cancer treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- DNA repair defects are linked to somatic mutations in tumors.
- These mutations can drive cancer growth or elicit a targeted immune response.
- Tumor-specific neoantigens (neoepitopes) arise from mutations and are presented on cancer cells.
Purpose of the Study:
- To explore the potential of exploiting DNA repair defects for cancer therapy.
- To investigate how inducing DNA damage and mutations can enhance anti-cancer immunity.
- To address the need for novel treatments for immunotherapy-resistant cancers.
Main Methods:
- Review of current understanding of DNA repair, mutations, and anti-tumor immunity.
- Analysis of the role of neoepitopes in cancer immunosurveillance.
- Examination of emerging combinatorial treatment strategies.
Main Results:
- Somatic mutations, particularly in protein-coding genes, generate neoepitopes.
- Immunotherapies like checkpoint inhibitors and vaccines can enhance anti-tumor immune responses.
- Combinatorial treatments aim to increase DNA damage and neoepitope expression.
Conclusions:
- Exploiting DNA repair defects offers a promising strategy to enhance anti-cancer immunity.
- Targeting DNA repair pathways could overcome resistance to current cancer therapies.
- This approach holds potential for developing more effective cancer treatments.
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