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Phenotype switching: plasticity and/or differentiation of stromal cells and their progenitors within the tumour microenvironment regulate tumour fate.

Periodic Reporting for period 4 - PhenoSwitch (Phenotype switching: plasticity and/or differentiation of stromal cells and their progenitors within the tumour microenvironment regulate tumour fate.)

Okres sprawozdawczy: 2022-10-01 do 2023-03-31

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.
The ERC PhenoSwitch proposal has made several discoveries most of which have already been published during the grant period, and others are currently in the process of publication. The highlights of these discoveries and their results are as follows:
a. We demonstrated that immune progenitor cells, referred to as monocytic dendritic progenitors (MDPs), are found in high numbers in the bone marrow of mice bearing metastatic disease when compared to mice bearing non-metastatic disease. We showed that the MDPs upon stimulation with IL-6 secreted by tumor cells, differentiate into immunosuppressive macrophages and facilitate metastasis. The blockade of IL6 resulted in a reduced number of metastases, in part due to the inhibition in the number of immunosuppressive macrophages.
b. While immunotherapy has made a paradigm shift in the treatment of cancer, many patients do not benefit from this treatment modality for reasons that are not clear. In our study, we found a pathway that can explain why some tumors do not respond to immune checkpoint blockade (ICB). Specifically, we showed that upon ICB treatment, the host generates a variety of factors that contribute to the recruitment of different immune cells to the tumor microenvironment, among them myeloid-derived suppressor cells (MDSCs). We also showed that among the factors induced in the plasma in response to ICB, is IL6 which hinders the anti-tumor effect of immunotherapy. Evidently, when we blocked IL6 in combination with ICB, we improved the outcome. This study paves the way for identifying biomarkers to predict immunotherapy outcomes.
c. In the context of chemotherapy, we focused on pancreatic cancer, a deadly form of cancer with limited treatment options. We demonstrated how chemotherapy supports an anti-tumor activity by specifically enriching a subset of progenitor cells in the bone marrow which ultimately induces anti-tumor immune cell activity. Specifically, we demonstrated that while chemotherapy may suppress/deplete immune cells in the bone marrow, it enriches the megakaryocytes-erythrocytes progenitors (MEPs), which in turn directly support anti-tumor T cell activity against tumor cells by secreting factors such as CXCL16 and CCL5. Overall, this study provides evidence of how MEPs, a progenitor cell subtype can alter the function of immune cells against tumors.
d. Immunotherapy has made a paradigm shift in the treatment of cancer, however, the major caveat is that not all patients benefit from this treatment, and there is an unmet need to identify those patients who can respond to therapy. We focused on immature myeloid cells in order to identify cell types that can predict outcomes. Following high throughput analysis, we identified a subset of neutrophils which are enriched in the tumors and blood of patients who can later on respond to treatment. We found how these cells support anti-tumor immunity. This work is currently being assessed in clinical samples to evaluate its translational potential
This is the last report of the project as it has been finalized. Based on this project not only that we identify a major role of immature immune cells in the tumor microenvironment to support tumor growth and metastasis, we also found that their function is critical for treatment outcomes.
During this project, we identified a subtype of neutrophils that can serve as a biomarker for immunotherapy outcomes. These neutrophils can be assessed in peripheral blood, while the current way to predict outcomes in patients treated with immunotherapy is by taking biopsies from the tumor and immunologically staining them with anti-PD1. Based on our findings, we have written a patent, that is in the national phase, and the examiners found it to be very innovative and non-obvious. We also received ERC-POC to study this subset of cells in clinical samples and to identify whether they can be used in the clinic. There are several advantages to using these cells as a biomarker for immunotherapy outcomes as opposed to the current clinical practice:
(a) The cells can be assessed in a liquid biopsy, from all patients (and not other biopsies).
(b) The cells serve as a pan-biomarker for many different cancers.
(c) The analysis is quick and results are obtained within an hour
(d) The analysis is carried out by a simple flow cytometry test, already an approved system for clinical use.
We believe that this project with the support of the ERC, will help many cancer patients in the near future.
the overall phenoswitch project