Human Keratinocyte Carcinomas Have Distinct Differences in Their Tumor-Associated Macrophages

Despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation, cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors. Whether these distinct features are associated with tumor-associated macrophages (TAMs) is largely unknown. The main goal of this study was to conduct a comprehensive analysis of density and polarization states of TAMs in SCCs versus BCCs. The role of lactic acid in TAM polarization in SCC versus BCC was examined. We found that SCCs have a higher density of CD68 TAMs compared to BCCs. TAMs in SCCs express higher levels of TAM-associated markers (arginase-1, MMP9, CD40 and CD127) than those in BCCs. Interestingly, differential expression of TAM-associated markers between SCCs and BCCs was reproduced in human monocytic THP-1 cells stimulated with SCC- or BCC-conditioned media. Analysis of soluble factor(s) in these tumors further revealed that SCCs have a significantly higher concentration of lactic acid than BCCs, and lactic acid was sufficient to upregulate TAM markers. Our results demonstrate that TAMs in SCCs versus BCCs differ in density and polarization states, which can be determined by soluble factors including tumor-derived lactic acid. These differences in TAMs may contribute to the distinct clinical behaviors of SCCs versus BCCs. Funding Statement: This work was supported by grants from NIH (5K08CA172580), Doris Duke Charitable Foundation (15-007374), and NIH Medical Scientist Training Program (T32 GM007205). Declaration of Interests: Authors report no conflicts of interest. Ethics Approval Statement: De-identified, discarded tissue was obtained consistent with the general requirements of the protocol approved by the Yale Human Investigations Committee (HIC#200002048).