Jiang Xiaodong, Wang Mike, Cyrus Nika, Yanez Diana A, Lacher Richard K, Rhebergen Anne Marie, Brokowski Carolyn, Galan Anjela, Book Samuel, Colegio Oscar R
Department of Dermatology, Yale University School of Medicine. New Haven, CT, 06520, USA.
Department of Pathology, Yale University School of Medicine. New Haven, CT, 06520, USA.
Heliyon. 2019 Aug 13;5(8):e02273. doi: 10.1016/j.heliyon.2019.e02273. eCollection 2019 Aug.
Cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) have different clinical behaviors, despite both being keratinocyte carcinomas mainly caused by ultraviolet radiation. 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 BCCs. The role of lactic acid in TAM polarization in SCC 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 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 BCCs. This work was supported by grants from the National Institutes of Health and the Doris Duke Charitable Foundation.
Few studies have studied tumor-associated macrophages in the context of SCC BCC. It has been demonstrated that macrophages mobilize to the epidermis after being exposed to ultraviolet-B radiation and produce interleukin-10 (IL-10). It has also been shown that the production of IL-10 results in the evasion of T cell-mediated immunity in BCCs and SCCs. However, the relationship between TAMs and the clinical behaviors of SCCs and BCCs remains largely unclear. Our study shows that despite their similar origins, human cutaneous SCCs and BCCs are considerably different in their TAMs. To our knowledge, these results provide the first evidence of differential TAM density and polarization in SCCs BCCs, which may contribute to their characteristic clinical behaviors. Future studies are necessary to elucidate the mechanisms by which TAMs influence these cancers with the goal of developing therapies tailored to each type of malignancy.
皮肤鳞状细胞癌（SCC）和基底细胞癌（BCC）具有不同的临床行为，尽管二者均为主要由紫外线辐射引起的角质形成细胞癌。这些明显特征是否与肿瘤相关巨噬细胞（TAM）有关在很大程度上尚不清楚。本研究的主要目的是全面分析SCC和BCC中TAM的密度和极化状态。研究了乳酸在SCC和BCC中TAM极化中的作用。我们发现，与BCC相比，SCC中CD68 + TAM的密度更高。SCC中的TAM比BCC中的TAM表达更高水平的TAM相关标志物（精氨酸酶-1、基质金属蛋白酶9、CD40和CD127）。有趣的是，在用SCC或BCC条件培养基刺激的人单核细胞THP-1细胞中再现了SCC和BCC之间TAM相关标志物的差异表达。对这些肿瘤中可溶性因子的分析进一步表明，SCC中乳酸的浓度明显高于BCC，并且乳酸足以上调TAM标志物。我们的结果表明，SCC和BCC中的TAM在密度和极化状态上存在差异，这可以由包括肿瘤衍生乳酸在内的可溶性因子决定。TAM的这些差异可能导致SCC和BCC不同的临床行为。本研究得到了美国国立卫生研究院和多丽丝·杜克慈善基金会的资助。
很少有研究在SCC和BCC的背景下研究肿瘤相关巨噬细胞。已经证明，巨噬细胞在暴露于紫外线B辐射后会迁移到表皮并产生白细胞介素-10（IL-10）。还表明，IL-10的产生导致BCC和SCC中T细胞介导的免疫逃避。然而，TAM与SCC和BCC临床行为之间的关系在很大程度上仍不清楚。我们的研究表明，尽管人类皮肤SCC和BCC起源相似，但它们的TAM有很大差异。据我们所知，这些结果首次证明了SCC和BCC中TAM密度和极化的差异，这可能导致它们独特的临床行为。未来有必要开展研究以阐明TAM影响这些癌症的机制，目标是开发针对每种恶性肿瘤类型的疗法。
