84P - Profiling of lipid-loaded macrophages in melanoma

Background

Macrophages represent the main infiltrating immune subset in most cancer types and tumor-associated macrophages (TAMs) sustain tumor growth, promote invasion and mediate immune suppression. Interestingly, a population of lipid-loaded macrophages has been recently identified in prostate cancer, colon cancer and melanoma. However, the mechanisms that drive lipid accumulation in macrophages and the functional impact of lipid-loading still need to be uncovered.

Methods

We profiled the cancer immune infiltrate in a murine model of melanoma and we performed bulk RNA sequencing of lipid-loaded macrophages to investigate pathways involved in lipid accumulation. We applied in vitro assays to dissect the interplay between macrophages and melanoma cells and we took advantage of immunofluorescence analysis to study the mechanisms responsible for lipid accumulation in tumor-conditioned macrophages.

Results

We confirmed that lipid accumulation is a feature of TAMs in melanoma and we observed that lipid-loaded macrophages express markers of immunosuppression, including arginase and PD-L1. Importantly, the abundance of lipid-loaded macrophages correlates with tumor size, suggesting their support to tumor progression. In vitro, cancer cells shift the polarization of macrophages toward a pro-tumoral state and augment their capability to accumulate lipid droplets when triggered with lipid species. In addition, autophagic flux resulted impaired in macrophages exposed to tumor cells, suggesting defective autophagy as a potential mechanism responsible for lipid accumulation. In the end, we observed that transcription factor EB (TFEB) is deregulated in tumor-conditioned macrophages, indicating a role of TFEB in promoting autophagy deficiency and lipid accumulation in TAMs.

Conclusions

Here we show that TAMs in melanoma accumulate lipids and acquire pro-tumorigenic and immunosuppressive features. Additionally, the inactivation of transcription factor EB promotes a defective autophagic machinery that could be relevant in lipid accumulation in TAMs. In this context, we believe that TFEB activation may prevent lipid accumulation thus potentially improving efficacy of current available immunotherapies and therefore representing a promising opportunity for cancer therapy.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Fondazione AIRC per la Ricerca sul Cancro.

Disclosure

All authors have declared no conflicts of interest.