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Updated: May 26, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Thiopurine therapy enhances immune checkpoint inhibitor efficacy in low-mutational burden melanoma: A promising
Loulieta Nazerai1, Christina Tsiavou1, Lina Vardouli1
1Melanoma Research Team, Danish Cancer Institute, Copenhagen 2100, Denmark.
Abstract:
A key limitation of immune checkpoint inhibitors (ICI) therapy is their reduced efficacy toward cancers with a low tumor mutational burden (TMB). Since low-TMB tumors express fewer neoantigens, they are less responsive to ICI therapy like anti-PD-1 and anti-CTLA-4. In preclinical immunocompetent mouse models of low-TMB melanoma, we recently demonstrated that exposure to 6-thioguanine (6TG) significantly improved tumor control by increasing TMB and creating a proinflammatory tumor microenvironment. The combination of 6TG with anti-PD-1 further improved tumor control, although it did not fully inhibit tumor growth. We here investigated additional ICI combinations, assessing anti-CTLA-4 with anti-PD-1 to improve efficacy. ICI eliminated tumors in 6TG-exposed mice when ICI treatment was initiated at tumor volumes of 20 mm3, stopped tumor growth at volumes of 120 mm3, and had no effect at volumes of 300 mm3. Finally, we showed that mice achieving complete tumor regression with 6TG and ICI treatment exhibited lasting immune memory, which effectively suppressed tumor growth at relapse upon re-exposure to tumor cells. These findings may pave the way to effective application of ICI to low-TMB cancers, when initiated at low tumor volume.
Insights
6-thioguanine (6TG) combined with immune checkpoint inhibitors (ICI) enhances tumor control in low-TMB melanoma models. Early treatment initiation at low tumor volumes is crucial for complete tumor regression and lasting immune memory.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in low tumor mutational burden (TMB) cancers due to fewer neoantigens.
- Low-TMB tumors are less responsive to therapies like anti-PD-1 and anti-CTLA-4.
- 6-thioguanine (6TG) has shown potential in preclinical models to increase TMB and promote a proinflammatory tumor microenvironment.
Purpose of the Study:
- To investigate the efficacy of combining 6TG with different ICI combinations (anti-CTLA-4 and anti-PD-1) in low-TMB melanoma.
- To determine the impact of treatment initiation timing and tumor volume on ICI efficacy.
- To assess the development of immune memory following successful tumor regression.
Main Methods:
- Utilized preclinical immunocompetent mouse models of low-TMB melanoma.
- Administered 6-thioguanine (6TG) followed by combinations of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors.
- Evaluated tumor control, TMB, tumor microenvironment changes, and immune memory responses at different tumor volumes and time points.
Main Results:
- 6TG treatment increased TMB and created a proinflammatory tumor microenvironment.
- Combination therapy of 6TG with ICI eliminated tumors when initiated at 20 mm³.
- Treatment stopped tumor growth at 120 mm³ but was ineffective at 300 mm³.
- Mice achieving complete regression developed lasting immune memory against tumor relapse.
Conclusions:
- Combining 6TG with ICI offers a promising strategy to improve treatment efficacy in low-TMB cancers.
- Early intervention at low tumor volumes is critical for achieving complete tumor regression and durable responses.
- The development of immune memory suggests potential for long-term protection against cancer recurrence.
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