Final Report Summary - INFLAMET (Mechanistic insights into the impact of tumor-associated neutrophils on metastatic breast cancer)
Metastatic disease accounts for over 90% of breast cancer-related deaths. Despite its devastating effects, metastatic disease is still poorly understood and incurable. We have studied the impact of the immune system on metastasis formation of breast cancer. Based on the strong association between accumulation of neutrophils in blood of cancer patients and metastasis formation, we set out to study the consequences of neutrophils in metastasis formation. Utilizing pre-clinical mouse models of spontaneous breast cancer metastasis that mimic the clinical course of metastatic disease in humans, we discovered that breast tumors induce the activation and accumulation of neutrophils in blood and distant organs. These neutrophils stimulated metastasis formation to lungs and lymph nodes by suppressing the anti-tumor function of other immune cells, called T cells. Inhibition of neutrophils in breast cancer-bearing mice resulted in a profound reduction of lymph node and lung metastases. We have also identified several factors that are secreted by breast tumors that induce the activation of pro-metastatic neutrophils. We have validated these findings using human datasets and immunoprofiling studies in breast cancer patients. Importantly, we have revealed a novel role for loss of the p53 gene in breast cancer cells as a key regulator of systemic inflammation in breast cancer. Breast tumors that have lost the p53 gene induce a strong activation of pro-metastatic systemic neutrophilic inflammation, in contrast to breast tumors that have a functional p53 gene. These insights illustrate the importance of the genetic makeup of cancer cells in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for cancer patients. In summary, our novel mechanistic insights obtained through this ERC consolidator project have contributed to the following two concepts 1) the importance of systemic inflammation on metastasis and proof-of-concept of targeting this process to interfere with metastatic disease in preclinical models; 2) the importance of the genetic makeup of cancer on the immune landscape. Our findings open new avenues for personalized immune intervention strategies for breast cancer patients with specific genetic aberrations.