Characterizing myeloid cells in the tumor environment - Implications for diagnostic and therapeutic approaches.

Abstract

Several pathologies including cancer are associated with dysregulated immune cells. Numerous studies have indicated an association between patient outcomes, therapy responses, and disease recurrence to prevalence and characteristics of different immune populations. Among them, myeloid cell populations exhibited remarkable functional heterogeneity and a range of functions that can influence multiple cancer hallmarks. Therapeutic strategies that target tumor immune cells have indicated promise. However, in solid tumors, the heterogenous and plastic nature of immune cells contributes considerably to challenges associated with clinical translation of these therapies. This highlights the need to further investigate characteristics, functions, and phenotypes of the different immune cells in cancer. This thesis includes three studies investigating the immune landscape of breast and colon cancer. Using the mouse breast cancer model, the distinct immune profiles of tumors with different metastatic potential (4T1-derived 67NR (nonmetastatic) and 66cl4 (metastatic) tumors) were investigated to reveal significant distinctions in myeloid cell populations. Metastatic tumors were associated with a higher number of distinct macrophages that had dampened capacity of antigen presentation and enhanced regulatory function. Non-metastatic and metastatic cells appeared to influence neutrophil activation and polarization differently. A tumor secreted cytokine- CXCL3, was identified as a contributing factor in the distinct immune landscape of metastatic 66cl4 tumors. Using the same mouse model, we further identified a higher number of Arg1+ immune cells associated with tumors with a high metastatic potential. An abundance of Arg1+ immune cells was confirmed in biopsies of aggressive breast cancer tumors with a high risk of metastasis. Combined these findings indicate that myeloid cells in tumors have several distinct properties that may influence the metastasis and aggressiveness of breast cancer. Enhanced expression of neutrophil markers was also observed in colorectal cancer biopsies, indicating infiltration of neutrophils in these tumors. Activation of the innate immune receptor Toll-like receptor 3 induced secretion of chemokines and neutrophil recruitment in vitro. TLR3 activation in colon cancer cells induced cytokines that modulated neutrophils to upregulate interferon-stimulated genes and further altered their surface expression of proteins which are associated with an anti-tumorigenic phenotype. TLR3 activation in colon cancer cells induced cytokines that modulated neutrophils to upregulate interferon-stimulated genes and further altered their surface expression of proteins which are associated with an anti-tumorigenic phenotype. Overall, findings from the three papers improve our understanding of myeloid cells in tumors. The work identified distinctions in the myeloid populations associated with tumors of different metastatic propensities. The proportion and characteristics of myeloid populations, and their activities in metastatic tumors appeared distinct from those in non-metastatic tumors. Triggering inflammation pathways in tumor cells can impact the neutrophil phenotype, which may have implications for cancer progression. These findings contribute to ongoing efforts that aim to exploit myeloid cells as prognostic markers and therapeutic targets. Finally, the thesis discusses implications of our findings in clinical management of cancer