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Abstract 1137: Unraveling spatially-dependent interactions of tumor-associated macrophage in the tumor microenvironment

Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA

Tumor-infiltrating lymphocytes (TIL) are a strong prognostic factor in cancer patient outcomes. This includes immune checkpoint blockade (ICB) of the PD-1/PD-L1 axis, where patients with a higher abundance of pre-treatment TILs respond more frequently. However, tumors often elaborate mechanisms to exclude TILs and/or suppress their function. Identifying negative regulators of TILs is thus of great importance to improve patient outcomes and increase the patient population that may benefit from ICB. Tumor-associated macrophages (TAM) are a known modulator of TIL activity but the interaction between the two cell types is typically characterized with in vitro experiments and spatially-agnostic sequencing, ignoring location-specific factors contributing to the interaction’s net effects. Interrogating the TAM-TIL interactions in an intact tumor microenvironment (TME) will uncover novel mechanisms responsible for TAM function and may be key to reversing TIL immunosuppression. Here we leverage bulk RNA-sequencing with histocytometry, a multiplex quantitative tissue imaging method, to spatially-resolve the TAM-TIL interactions in intact human metastatic melanoma microenvironments. Bulk sequencing distinguishes tumor samples by high and low enrichment of lymphocyte gene sets, with additional sub-stratification by macrophage enrichment. Modular repertoire analysis implicates an interferon response in the differential lymphocyte enrichment, but does not address macrophage-dependent effects. Drawing from physical chemistry concepts, our spatial analyses of cell-cell interactions from histocytometry reveals distinct TAM populations potentially regulating TIL activity. Phagocytic TAMs in the tumor and non-phagocytic TAMs in the stroma physically contact T-cells, with the former interaction strongly correlated with lymphocyte enrichment and T-cell infiltration. Local and regional TAM phagocytosis affinities estimated by the Langmuir adsorption model further detail the nature of this interaction within the tumor, as well as the role of macrophage phagocytosis in regulating TILs. We demonstrate linear models integrating bulk sequencing and spatial metrics to quantify the relationships between genetics, cell-cell interactions, and T-cell invasiveness. Our work unravels important TAM interactions that shape the TME which have not been previously appreciated, providing novel insight into the forces driving T-cell exclusion and revealing new TAM biology to explore further.

Citation Format: Victor Wang, Jan Martinek, Hannah M. Brookes, Kyung In Kim, Karolina Palucka, Jeff Chuang. Unraveling spatially-dependent interactions of tumor-associated macrophage in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1137.