TIM3+ breast cancer cells license immune evasion during micrometastasis outbreak
Catalina Rozalén, Irene Sangrador, Silvia Avalle, Sandra Blasco-Benito, Panagiota Tzortzi, María Sanz‐Flores, José Ángel Palomeque, Pau Torren-Duran, Mariona Dalmau Montalà, Héléna Brunel, Albert Coll-Manzano, Iván Pérez-Núñez, Tamara Martos, Sònia Servitja, Sandra Pérez‐Buira, José Ignacio Chacón, Ángel Guerrero‐Zotano, Eduardo Martínez de Dueñas, Yolanda Guillén, Laura Comerma, Begoña Bermejo, Anna Bigas, María Casanova-Acebes, Anna Alemany, Federico Rojo, Joan Albanell, Toni Celià-Terrassa
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.