Characterization of immunosuppressive myeloid cells in Merkel cell carcinoma: correlation with resistance to PD-1 pathway blockade

Merkelcell.org Summary

Myeloid cells are a group of special blood cells that are important for our body’s immune response. To better understand how our immune system fights off MCC, researchers investigated what type of myeloid cells are important in MCC tumors. They found that macrophages, a type of myeloid cell that eat dying cells, were abundant inside and around the tumor. Like some other cancers, the types of macrophages found in MCC tumors are immunosuppressive, meaning they work to stop other immune cells fighting the tumor cells. Having too many of these macrophages may make it less likely for someone to benefit from immunotherapy. This may be due to the macrophages canceling out the work of CD8 T-cells (our body’s “killer T-cells” that act like soldiers). Ongoing research to identify areas to shut down these immunosuppressive macrophages may help patients respond better to immunotherapy.

Abstract

Purpose: Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only ~50% to PD-(L)1 blockade suggesting barriers to T cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored.

Experimental design: We utilized single cell transcriptomics from 9 MCC patients and multiplex-immunohistochemistry staining of 54 patients’ pre-immunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response.

Results: Single cell transcriptomics identified tumor-associated macrophages (TAMs) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 pre-immunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T-cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms.

Conclusions: This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration.