Abstract 491P
Background
Definite polarization of tumor associated macrophages (TAMs) sustains tumorigenesis and cancer progression. Dysregulation of lipid metabolism hold a potential role in the acquisition of immunosuppressive phenotype and the overcoming of tumor immune surveillance. The aim of the study was to investigate the crosstalk between dyslipidemic myeloid cells and adaptive immunity in early and late colorectal cancer (CRC).
Methods
Morphological parameters and phenotypic characterization of TAMs were evaluated in lesions and unaffected mucosa of i) APC-driven polyposis (n=100), ii) sporadic adenomas (n=50), iii) T2-4, N0-1 CRC (n=100), by histopathology and immunohistochemistry. Single-cells suspensions obtained from prospective tumor or polyps vs. mucosa samples were analyzed for multiple myeloid, B- and T- cell subset, by multiparametric flow cytometry analysis.
Results
A subset of large, CD68bright CD163dim HLA-DR+ macrophages, engulfed with neutral lipid droplets, were selectively found within lamina propria, at the “root” of 45% hereditary and 25% sporadic polyps. Present in a barrier-like distribution in 70% CRC lesions, lipid-engulfed macrophages were absent in unaffected colon mucosa. These cells showed expression of CD36 and PD-L1, and were found in close proximity of CD3+ PD1+ T-cells. A lipophilic fluorescent dye BODIPY 493/503 confirmed an enhanced lipid accumulation in a subset of TAMs together with hallmark phenotype, including CD206 and CX3CR1. The presence of these cells was associated with higher frequencies of regulatory CD4+, exhausted Tim3+ PD-1+ CD8+, and decreased γδ T-cells.
Conclusions
Differences between mucosa and CRC lesions in relation to the presence of lipid-engulfed macrophages indicate that dysregulation of lipid metabolism reprograms their functional polarization, suppressing T cell adaptive response to help transformed epithelial cells in escaping antitumor immunosurveillance. These findings might provide new metabolic druggable pathways to enhance antitumor immunity for both prevention and treatment of CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Dr. Licia Rivoltini, Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori Milano.
Funding
Pezcoller Foundation.
Disclosure
All authors have declared no conflicts of interest.