Immune-cancer cell interactions in metastatic niches upon chemotherapy

Neoadjuvant chemotherapy (NACT) is the standard-of-care for the management of triple-negative breast cancer (TNBC), but despite its successes approximately 25% of patients with advanced disease will fail to respond or will eventually relapse, thus increasing the likelihood of metastasis. There is therefore an immediate need for alternative and improved treatment strategies. While research has largely focused on resistance mechanisms at the cancer cell level, it has become apparent that stromal microenvironment alterations are important in modulating tumour responses to therapy and in regulating metastasis formation. Our recent research has revealed that primary tumours exposed to NACT communicate with non-cancerous stromal cells at pre-metastatic niches through the release of pro-metastatic extracellular vesicles (EVs), thus limiting the therapeutic efficacy of NACT. The goal of this proposal is to reveal how NACT modifies the immune landscape in the metastatic niche, and to discover the immune subsets modulating therapy-induced metastasis during the different stages of the metastatic process. Using single-cell transcriptomics, computational as well as in vivo and in vitro approaches, we aim to identify distinct myeloid-derived sub-populations that could be therapeutically exploited to improve chemotherapeutic responses of patients with metastatic disease, thus providing the basis for translating this work into an improved treatment for TNBC.

Despite the significant advancements in cancer treatment, metastasis remains the primary cause of cancer-related deaths. Therefore, understanding the molecular and cellular cues behind this process is crucial for new and more effective therapeutic strategies. Unlike primary tumours, where the heterogeneity of myeloid cells infiltrating the tissue has been well studied, our current knowledge regarding immune cell regulation and heterogeneity in metastatic niches, over time and space is limited.

Using single-cell RNA sequencing analysis in metastatic lesions of mouse models of breast cancer, my work has identified a myeloid-derived immune cell cluster as a component of the pulmonary metastatic niche. With the generous support of the Beug Foundation, we were able to perform bioinformatic analyses and preclinical studies to further elucidate their function in modulating the metastatic process. Importantly, our work revealed that these cells crosstalk with distinct monocytic clusters thus conferring them a tumour-suppressive phenotype. Furthermore, lung infiltration by these cells increases in response to chemotherapy, suggesting that these cells may indeed be implicated in metastasis formation post-therapy.  Currently, we are performing loss-of-function studies in vivo to delineate their mechanism of action and to identify new therapeutic targets to combat metastatic breast cancer.

These preliminary data obtained with the support of the Beug Foundation have strengthened my research proposal for competitive grant applications and have allowed me to secure an EMBO Installation Grant to fund my research for the next years. I am extremely grateful to the Beug Foundation for their support with this project but most importantly for believing in me and my research.

keklikoglou@uoc.gr

www.biology.uoc.gr