Dynamics and function of peritoneal myeloid cells during colorectal cancer peritoneal dissemination and implications for immunotherapy

ABSTRACT Gastrointestinal (GI) cancer peritoneal metastasis is one of the most lethal, clinically challenging, and treatment- resistant manifestations. The peritoneal cavity, a potential space lined by the serous membrane known as the peritoneum, is divided into the parietal peritoneum covering the abdominal walls and diaphragm, and the visceral peritoneum enveloping the abdominal organs. Studies on ovarian cancer, a non-GI cancer that frequently develops peritoneal metastasis, have shown that omental macrophages, part of the visceral peritoneum, can promote metastasis in mouse models. However, the relevance of these findings to human GI cancer peritoneal metastasis remains largely unexplored. Additionally, the peritoneal fluid within the cavity harbors a diverse array of immune cells, including both myeloid cells and lymphocytes. My recent study characterized the immune cell landscape in the normal human peritoneal cavity. Contrary to our knowledge from mouse models, where GATA6+ large peritoneal macrophages are predominant, these cells are rare in humans. Instead, the human peritoneal cavity is enriched with LYVE1+CD206+ macrophages, known for their potential immunoinhibitory functions. Moreover, normal human peritoneal cavities contain abundant dendritic cells (DCs), especially the CD1C+ DC2s. Despite these findings, the roles and impacts of these peritoneal myeloid cells on GI cancer progression, T-cell responses, and the effectiveness of immunotherapy are still not well understood. Therefore, this research proposal focuses on colorectal cancer (CRC), the most prevalent and lethal GI cancer in the United States, and aims to elucidate the unique roles of myeloid cells within the peritoneal cavity and peritoneum during CRC peritoneal metastasis. Informed by our previous findings that mouse and human tissues may have differing immune cell compositions, this study will commence by profiling immune responses in patients, ensuring that the findings are translational and clinically relevant. The initial efforts will determine the immune cell phenotypical changes within the peritoneal fluid and peritoneum during CRC peritoneal dissemination to identify the peritoneal metastasis-specific immune responses. Given the established role of LYVE1+ macrophages and monocytes in tumor progression and their prevalence in the human peritoneal cavity, mouse models will be employed in parallel to further investigate their functions during CRC peritoneal metastasis. Building on my PhD and postdoctoral training, this study aims to further track the trafficking of peritoneal myeloid cells and their interactions with T cells to clarify their roles in anti-tumor T cell responses and immunotherapy, setting the stage for my career as an independent researcher. The ultimate goal of this proposal is to develop a deep understanding of the immunological interplay within the peritoneal cavity during GI cancer metastasis, potentially revolutionizing our approach to immunotherapy by targeting these dynamics more effectively.