Cancer therapy, particularly in advanced metastatic stages, is limited in its efficacy, therefore it necessitates a comprehensive reevaluation of current approaches in order to improve therapy outcomes. While the majority of previous studies focused on the intrinsic characteristics of cancer cells to facilitate uncontrolled proliferation and dissemination from the primary tumor therefore supporting metastasis, recent studies suggest that the microenvironment of the tumor contributes to the growth of the tumor by actively generating pro-tumorigenic factors and cells which impact the cancer cells. Specifically, the stromal microenvironment, consisting predominantly of fibroblasts, endothelial cells, immune cells, adipose cells, and mesenchymal cells, plays a pivotal role in modulating the features of cancer cells and the trajectory of tumor development.
In our proposed research, we sought to investigate the function of stromal cells in the tumor microenvironment, with an emphasis on a subset of undifferentiated or progenitor immune cells. We asked how these cells contribute to tumor growth, and what is their differentiation pattern which promotes tumorigenesis and metastasis. Notably, cancer cells are postulated to induce the differentiation of these progenitor subsets, thus initiating a phenotypic and functional transition that skews them toward a tumor-promoting phenotype. Consequently, this cascade amplifies tumor cell aggressiveness and fosters the dissemination of cancer cells to distant sites.
Throughout this research period, we employed cutting-edge high-throughput technologies to meticulously trace the lineage, differentiation, and commitment of immune progenitor cells and their role in tumor progression and metastasis. We also searched for changes in these cells during treatment with anti-cancer drugs including chemotherapy and immunotherapy based on immune checkpoint blockade. Our research demonstrates that in both mice and man, immune progenitor cells can play a significant role in the tumor by differentiating at most to immunosuppressive cells, such as immunosuppressive macrophages and myeloid-derived suppressor cells. We also showed that a subset of these cells may play a completely different role, and therefore can serve as a biomarker for immunotherapy outcome. Overall, this research unraveled novel strategies for hindering the transition to a tumor-promoting phenotype and maintaining a tumor-restricting stromal microenvironment in both spontaneously growing tumors and after therapy. Some of the results of this study are currently being translated into innovative tools for predictive assessment and pharmacological interventions aimed at inhibiting tumor growth.
