Tumor Microenvironment in Cancer Progression

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The goal of this project is to elucidate the microenvironmental regulation of cancer progression- how the host allows cancer to survive, grow and spread. By outlining the stepwise events in the microenvironmental changes (the soil that supports the seed) that contribute to metastasis we propose an approach to effectively treat cancer and limit or reverse metastatic progression. Targeting unique mutations for individual cancer cells hold challenges given the adaptability of the tumor cells. Our investigations in murine studies of the earliest changes in the microenvironment has delineated the key components of the pre-metastatic niche and extracellular matrix remodeling and the functional role of myeloid cells in establishing an immune suppressive microenvironment. Matrix remodeling is the process where the stromal cells of the body lay down the matrix that serve as the glue between cells and help give shape to our organs. These noncellular components are as important as the cells themselves. These matrix components are also like the roads and can be important in transmitting signals between cells and promoting communication between different sites in the body. We are studying these matrix components and their changes in cancer. We have developed a system to change these matrix components which are often very thick in cancer. By making changes to it we can improve how our therapies such as chemotherapy, cell therapy, antibodies can get into the tumor and effectively target the tumor cells. We have done experiments that this matrix remodeling therapy can help patients with fibrosis which is a major health problem with very little effective therapies. This line of work is very productive and can improve care for patients. The other major component of the microenvironment that we study are the myeloid cells which are immune cells that come from the bone marrow and play an integral role in regulating T cell responses (Giles et al Cancer Research 2016; Kaczanowska et al Cell 2021, Nature Cancer 2024). We have found that if we manipulate these microenvironments through changing the activities of these immune cells and wound healing behaviors we can limit or prevent cancer spread. We have new data based on machine learning and big data analysis of single cell sequencing that demonstrates the process of cancer progression involves education of host immune system and wound healing responses to favor the cancers growth, survival and spread even with treatment. The key features of this systemic educated response to cancer can serve as a biomarker for metastasis and hold promise to help stratify patients at risk for cancer progression and provide avenues for establishing models for which patients can have less therapies and therefore less toxicities and which patients need more or different therapeutic approaches. Some patients at highest risk for the cancer to return or spread will benefit from therapies modulating their own host immune response or wound healing that can be more effective than the whack a mole game with the tumor cells themselves. We have several ongoing studies to effectively test these hypotheses in both retrospective analyses as well as prospective studies in solid tumor cancers. In addition to understanding how these cells can serve as a biomarker to better stratify patients, the myeloid cells in this signature have a cell state that holds important functional roles in cancer progression. Myeloid cells are highly potent immune cells that can modulate T and NK cell activity. They also interact effectively with many cells in the body and can navigate in any tissue in the body. We are actively focused on understadning the function of these cells better and their role in many diseases especially chronic diseases not only cancers but autoimmune disease such as inflammatory bowel disease, diabetes, other diseases such as atherosclerosis, alzheimer's disease and obesity. Our research shows these myeloid cells can take up bits of cell membrane from other cells to present to the immune system as foreign and thereby contribute to autoimmunity pathology or can turn off the immune response allowing cancer cells to grow and spread unnoticed. Studies to delineate the functions and mechanism of this behavior of these cells are ongoing and are leading to new approaches to treat cancer and these chronic diseases. We have on-going investigations examining the small molecular inhibitor PLX3397 that targets CSF1R found on these myeloid cells, cKit and FLT3-ITD. We have initiated and completed the Phase I dose escalation of PLX3397 in pediatric and adolescent patients with recurrent or refractory tumors (Boal et al Clinical Cancer Research). We are now focused on Turalio (PLX3397) for pediatric tenosynovial giant cell tumors. We are the only pediatric trial for these children who often suffer from pain and dysfunction in these joints are with this therapy provide opportunity to walk again, regain function and resume everyday childhood activities. This is a huge win for the families and although a rare tumor makes a major difference in these individuals lives. We are assessing efficacy and biomarkers in these patients currently with the plan to submit a proposal to FDA for approval of this drug in children. We have also developed a new cell therapy approach platform to reprogram these recruited immune suppressive myeloid cells by introducing genetically engineered myeloid cells (GEMys) that express IL12. These IL12 GEMys can reverse the immune suppression program in the pre-metastatic niche and lead to inhibition of metastatic progression and significantly prolong overall survival in highly metastatic murine models (Kaczanowska et al Cell 2021). IL12 GEMys when given following fludarabine and cyclophosphamide tumor bearing hosts lead to long term cures in these metastatic pre-clinical models (Kaczanowska et al Cell 2021). We have developed a clinical protocol for human IL12 GEMys and have generated a functional manufacturing pipeline for human IL12 GEMys for the first in human phase I trial planned. We have performed IND enabling studies and completed process quality runs for the CMC package for FDA. In addition we have performed deep tumor and metastatic microenvironment analyses of a syngeneic orthotopic model of osteosarcoma and found parallels with our rhabdomyosarcoma and breast carcinoma models. These consistent microenvironmental changes in pre-, early and late metastatic sites suggest that the metastatic microenvironment is not only a viable therapeutic target but may hold more consistent and applicable modifications that can limit the metastatic process in many different genomically diverse cancers. We have recently found that IL12 GEMys have efficacy in alleviating myeloid mediated immune suppression in osteosarcoma which we determined is a heavily myeloid dense cancer. The lack of efficacy of checkpoint blockade therapy and other T cell based therapies in Osteosarcoma may be due to this dense immunosuppressive myeloid cell infiltration. More recently we have translated the findings in murine studies to study metastatic microenvironment in patients with osteosarcoma and adrenocortical carcinoma and find similar changes in the microenvironmental components including abundant and diverse myeloid populations including recruited monocyte populations that have gene expression associated with myeloid derived suppressor cells. We are very eager to open this first in human clinical trial of novel myeloid cell therapy this year. These cell therapy platforms to impact immune system and the matrix stroma can help in the treatment of cancer and other chronic diseases. We are also making progress in modifying these myeloid cells to express CXCR3 and trogocytose to modulate antigen presentation and improve anti-tumor immunity.