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TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak
Catalina Rozalén1, Irene Sangrador1, Silvia Avalle1
1Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain.
Abstract:
In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3+ tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3+ tumor cells in BC metastasis and TIM3+ tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.
Insights
T cell immunoglobulin and mucin domain 3 (TIM3) promotes breast cancer micrometastasis survival and immune escape. Blocking TIM3 may offer a therapeutic strategy against early-stage, subclinical metastasis.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis Research
Background:
- Tumor-immune interactions during early micrometastasis are not well understood.
- Identifying vulnerabilities in micrometastases is crucial for developing metastasis therapies.
- Targeting early-stage metastasis before progression to macrometastasis offers therapeutic opportunities.
Purpose of the Study:
- To investigate the role of T cell immunoglobulin and mucin domain 3 (TIM3) in breast cancer (BC) micrometastasis.
- To elucidate the mechanisms by which TIM3 influences tumor cell survival, stemness, and immune evasion during early metastasis.
- To evaluate the therapeutic potential of TIM3 blockade in preclinical models of BC metastasis.
Main Methods:
- Utilized breast cancer (BC) metastasis mouse models to study micrometastasis dynamics.
- Analyzed TIM3 expression in tumor cells within micrometastases.
- Investigated the molecular mechanisms involving β-catenin/interleukin-1β (IL-1β) signaling and T cell populations (γδ T cells and CD8 T cells).
- Correlated TIM3 expression with clinical data from BC patients.
- Tested the efficacy of (neo)adjuvant TIM3 blockade in reducing metastatic burden.
Main Results:
- TIM3 is significantly upregulated in breast cancer micrometastases, promoting tumor cell survival, stemness, and immune escape.
- TIM3+ tumor cells are preferentially selected during the early stages of micrometastasis seeding.
- TIM3 activation enhances β-catenin/IL-1β signaling, fostering stemness and immune evasion by promoting immunosuppressive γδ T cells and reducing CD8 T cells.
- Increased TIM3+ tumor cells in BC metastasis correlate with poor patient outcomes.
- (Neo)adjuvant TIM3 blockade effectively reduced metastatic seeding and incidence in preclinical models.
Conclusions:
- TIM3 plays a critical role in promoting breast cancer micrometastasis through enhanced survival, stemness, and immune evasion.
- TIM3+ tumor cells represent a potential biomarker for poor prognosis in breast cancer patients.
- TIM3 blockade emerges as a promising therapeutic strategy for targeting subclinical metastasis and preventing overt disease progression.
