Dual Role of Tamoxifen in Enhancing STING and CEACAM1 Expression to Prime a Favorable Tumor Microenvironment for
Marvin Angelo E Aberin1,2, Saurabh Singh3, Soumya Chatterjee3
1Taiwan International Graduate Program in Molecular Medicine, Academia Sinica and National Yang Ming Chiao Tung University, Taipei, Taiwan.
Abstract:
Despite advancements in immune checkpoint blockade (ICB) therapy, breast cancer shows limited response to anti-PD1/PD-L1 treatments, emphasizing the need for alternative ICB targets. Here, we reveal that endocrine therapeutics, specifically tamoxifen, create an immunosuppressive yet primed tumor microenvironment conducive to anti-TIM3 immunotherapy. Tamoxifen induces mitochondrial DNA damage and disrupts the RACK7/KDM5C histone demethylase complex, resulting in STING accumulation and activation of the type I interferon (IFN-I) pathway, thereby fostering an immunogenic tumor microenvironment. However, tamoxifen also elevates CEACAM1 expression via a RACK7/KDM5C axis, driving T-cell exhaustion and limiting tumor elimination. This dual effect of tamoxifen - promoting STING-mediated immunogenicity while upregulating CEACAM1 expression - shapes the tumor-immune microenvironment in both ER-positive and ER-negative tumors. Notably, combining anti-TIM3 immunotherapy with tamoxifen mitigates its immunosuppressive effects, potentially enhancing ICB efficacy. Our findings highlight the therapeutic potential of integrating anti-TIM3 immunotherapy with endocrine therapy to improve outcomes for breast cancer patients.
Insights
Tamoxifen primes the tumor microenvironment for anti-TIM3 immunotherapy in breast cancer by activating immune pathways and upregulating CEACAM1. Combining tamoxifen with anti-TIM3 therapy may improve treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Breast cancer exhibits limited response to current anti-PD1/PD-L1 immune checkpoint blockade (ICB) therapies.
- There is a critical need for novel ICB targets and therapeutic strategies to enhance treatment efficacy.
Purpose of the Study:
- To investigate the dual role of tamoxifen in shaping the tumor microenvironment.
- To explore the potential of combining tamoxifen with anti-TIM3 immunotherapy for breast cancer treatment.
Main Methods:
- Analysis of tamoxifen's effects on mitochondrial DNA damage, RACK7/KDM5C complex, STING activation, and type I interferon (IFN-I) pathway.
- Assessment of CEACAM1 expression and its impact on T-cell exhaustion.
- Evaluation of combined tamoxifen and anti-TIM3 immunotherapy in preclinical models.
Main Results:
- Tamoxifen induces mitochondrial DNA damage, leading to STING accumulation and type I interferon pathway activation, enhancing tumor immunogenicity.
- Tamoxifen also upregulates CEACAM1 via the RACK7/KDM5C axis, causing T-cell exhaustion and limiting tumor elimination.
- Combining tamoxifen with anti-TIM3 immunotherapy counteracted the immunosuppressive effects, showing potential for improved efficacy in both ER-positive and ER-negative breast tumors.
Conclusions:
- Tamoxifen creates a complex tumor microenvironment with both immunogenic and immunosuppressive properties.
- Targeting TIM-3 in combination with tamoxifen represents a promising therapeutic strategy for breast cancer.
- This combination therapy has the potential to overcome resistance to current ICB treatments and improve patient outcomes.
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