Transient activation of tumoral DNA damage tolerance pathway coupled with immune checkpoint blockade exerts durable tumor regression in mouse melanoma
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Updated: Dec 3, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Ming Zhuo1, Falih M Gorgun1, Douglas S Tyler1
1Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
Abstract:
Major advances in cancer therapy rely on engagement of the patient's immune system and suppression of mechanisms that impede the antitumor immune response. Among the most notable is immune checkpoint blockade (ICB) therapy that releases immune cells from suppression. Although ICB has had significant success particularly in melanoma, it eradicates tumors in subsets of patients and sequencing data across different cancers suggest that tumors with high mutational loads are more likely to respond to ICB. This is consistent with the premise that greater tumoral mutational loads contribute to formation of neoantigens that spur the body's antitumor immune response. Prompted by strong evidence supporting the therapeutic benefits of neoantigens in the context of ICB, we have developed a mouse melanoma combination treatment, where intratumoral administration of DNA-damaging drug transiently activates intrinsic mutagenic DNA damage tolerance pathway and improves success rates of ICB. Using the YUMM1.7 cells melanoma model, we demonstrate that intratumoral delivery of cisplatin activates translesion synthesis DNA polymerases-catalyzed DNA synthesis on damaged DNA, which when coupled with ICB regimen, elicits durable tumor regression. We expect that this new combination protocol affords insights with clinical relevance that will help expand the range of patients who benefit from ICB therapy.
Insights
This study shows that combining a DNA-damaging drug with immune checkpoint blockade (ICB) therapy can enhance tumor regression in melanoma. This approach increases neoantigens, potentially expanding ICB benefits to more cancer patients.
Area of Science:
- Oncology
- Immunology
- Cancer Genetics
Background:
- Cancer therapy advances focus on harnessing the immune system, with immune checkpoint blockade (ICB) releasing immune cells from suppression.
- ICB shows success in melanoma but benefits only subsets of patients, with high tumor mutational loads correlating with better response.
- Increased tumor mutational burden is thought to enhance neoantigen formation, stimulating the body's antitumor immune response.
Purpose of the Study:
- To develop a novel combination treatment for melanoma by enhancing neoantigen formation to improve ICB efficacy.
- To investigate the synergistic effects of a DNA-damaging drug and ICB in a preclinical melanoma model.
Main Methods:
- Developed a combination therapy involving intratumoral administration of a DNA-damaging drug and ICB.
- Utilized the YUMM1.7 mouse melanoma model for treatment efficacy assessment.
- Administered cisplatin intratumorally to activate DNA damage tolerance pathways and translesion synthesis.
Main Results:
- Intratumoral cisplatin administration activated translesion synthesis DNA polymerases on damaged DNA.
- The combination of cisplatin and ICB elicited durable tumor regression in the YUMM1.7 melanoma model.
- This approach demonstrated improved success rates for ICB therapy.
Conclusions:
- Combining DNA-damaging agents with ICB therapy can enhance antitumor immune responses.
- This novel combination strategy shows potential for increasing the efficacy of ICB in melanoma.
- The findings offer insights for expanding ICB benefits to a broader patient population.
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