Delineating the myeloid-centric immunosuppressive crosstalk as targets for prognosis and therapy in neuroendocrine tumors

Project Summary / Abstract Neuroendocrine tumors (NETs) that are clinically and pathologically similar display significant differences in disease progression, therapeutic response, and overall survival. The limited accuracy of current prognostic biomarkers is a major unmet clinical need, particularly in a tumor type rapidly rising in prevalence and incidence.

While genetic drivers have been identified, these genetic alterations are limited to cancer cells and do not provide a systematic assessment of information encoded within the intact tumor microenvironment (TME), including the role of the tumor architecture and the spatially organized immunological processes. For example, while emerging

evidence proposes a key role for tumor-associated macrophages (TAMs) in orchestrating an immunosuppressive TME, patient-specific factors that mediate cell-to-cell interactions and localized chemokine and cytokine signaling in NETs are currently unknown. To address this knowledge gap, work from our group on

single-cell transcriptomic profiling of NETs has established that TAMs display an adverse continuum of cell states (i.e. not separated into the historical M1 or M2 groupings), while expressing tumor-specific chemokines and cytokines involved in regulating key immune pathways. Our findings highlight the significant heterogeneity within

the myeloid compartments of NETs, particularly TAMs, and may offer potential promising targets for prognosis and therapy. However, unlocking this potential requires the systematic understanding of the spatial distributions and interactions of these different macrophage cell populations with both the cancer cell and lymphoid cell

populations, which together - as a multi-cellular system - dictate immunosuppression or activation. These intricate spatial insights are still majorly lacking and obtaining them is only recently possible with the advent of new spatial technologies. To understand the underlying processes that drive NET progression, as well as reveal

potential therapeutic vulnerabilities, we will test our hypothesis across two mutually reinforcing aims. In Aim 1, we will identify the exact spatial composition, architecture and cellular crosstalk of the tumor and TME of archival NETs and connect the obtained information with macrophage-centric signaling and processes. In Aim 2, we will

determine if systematic spatial distributions and interactions of the macrophage cell populations and NET- specific chemokine profiles are associated with disease outcomes in NETs. The successful implementation of the proposed studies could provide innovative and data-driven insights into complex macrophage biology and

concurrently establish high-dimensional profiling of the TME as clinical biomarkers, thereby transforming prognostic stratification and clinical management for patients with NETs and potentially identifying novel druggable targets within the tumor as a whole.