Pro-metastatic systemic inflammation and the genetic make-up of cancer
Cancer-associated systemic inflammation is strongly linked with poor disease outcome in cancer patients. One of the long-standing research lines in my lab is focused on how primary mammary tumors hijack the immune system to facilitate metastatic spread. Utilizing mouse tumor models that faithfully recapitulate human breast tumorigenesis, we discovered how mammary tumors induce a systemic inflammatory response involving gamma delta T cells and immunosuppressive neutrophils that facilitate metastasis formation (Coffelt et al. Nature 2015; Kersten et al. Oncoimmunology 2017). More recently, we became interested in studying the mechanisms underlying the inter-patient heterogeneity in composition and activation status of the immune landscape. To determine how systemic neutrophilic inflammation is influenced by genetic aberrations in mammary tumors, we collaborated with Prof. Jos Jonkers and utilized a panel of 16 genetically engineered mouse tumor models (GEMMs) for breast cancer that harbor different tissue-specific mutations. We revealed that loss of p53 in breast cancer cells drives pro-metastatic systemic neutrophilic inflammation in a Wnt-dependent manner (Wellenstein et al. Nature 2019), illustrating that common genetic drivers of breast cancer influence the crosstalk with the immune system. We are currently extending this research to other genetic drivers of breast cancer. These insights will set the stage for tailoring immunomodulatory therapies to the DNA code of tumors of individual patients.
Dissecting the impact of the immune system on the efficacy of anti-cancer therapies
There is a growing realization that the immune system influences the success of cancer therapies, however, the exact underlying mechanisms are largely unknown. My lab studies the involvement of tumor-associated myeloid immune cells on the efficacy of chemo- and immuno-therapy response in breast cancer. While the adaptive immune system does not affect the outcome of chemotherapy against de novo mammary tumors in our preclinical mouse mammary tumor models (Ciampricotti et al. Nature Medicine 2012), we discovered that therapeutic targeting of macrophages improves chemotherapy response by unleashing type I IFN signaling. Simultaneous elimination of immunosuppressive neutrophils was required to engage an efficacious anti-tumor immune response that further improved therapeutic benefit of cisplatin (Salvagno et al. Nature Cell Biology 2019). We are currently evaluating whether the success of immune checkpoint inhibition in metastatic breast cancer can be improved by relieving tumor-induced immunosuppression. By gaining mechanistic insights into the involvement of the immune system in anti-cancer therapies, we aim to contribute to the rational design of effective immunomodulatory strategies to fight breast cancer
Clinical translation
Besides our preclinical research activities, my team closely collaborates with medical oncologist and researcher Marleen Kok (NKI/AVL) to comprehensively profile the peripheral immune landscape of breast cancer patients treated with immune checkpoint inhibitors, with the aim to identify immune-parameters associated with immunotherapy response and to gain a deeper understanding of the complex cancer-immune crosstalk in breast cancer patients.