Hematology/Oncology Division and Center for Cell-Based Therapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Laboratory of Inflammation and Pain, Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Cancer Immunol Res. 2016 Apr;4(4):312-22. doi: 10.1158/2326-6066.CIR-15-0170. Epub 2016 Jan 27.
Survivors from sepsis are in an immunosuppressed state that is associated with higher long-term mortality and risk of opportunistic infections. Whether these factors contribute to neoplastic proliferation, however, remains unclear. Tumor-associated macrophages (TAM) can support malignant cell proliferation, survival, and angiogenesis. We addressed the relationship between the post-sepsis state, tumor progression and TAM accumulation, and phenotypic and genetic profile, using a mouse model of sepsis resolution and then B16 melanoma in mice. In addition, we measured the serum concentrations of TNFα, TGFβ, CCL2, and CXCL12 and determined the effect of in vivo CXCR4/CXCL12 inhibition in this context. Mice that survived sepsis showed increased tumor progression both in the short and long term, and survival times were shorter. TAM accumulation, TAM local proliferation, and serum concentrations of TGFβ, CXCL12, and TNFα were increased. Naïve mice inoculated with B16 together with macrophages from post-sepsis mice also had faster tumor progression and shorter survival. Post-sepsis TAMs had less expression of MHC-II and leukocyte activation-related genes. Inhibition of CXCR4/CXCL12 prevented the post-sepsis-induced tumor progression, TAM accumulation, and TAM in situ proliferation. Collectively, our data show that the post-sepsis state was associated with TAM accumulation through CXCR4/CXCL12, which contributed to B16 melanoma progression.
脓毒症幸存者处于免疫抑制状态，与长期高死亡率和机会性感染风险相关。然而，这些因素是否导致肿瘤增殖尚不清楚。肿瘤相关巨噬细胞（TAM）可以支持恶性细胞增殖、存活和血管生成。我们使用脓毒症消退的小鼠模型和随后的 B16 黑色素瘤在小鼠中研究了脓毒症后状态、肿瘤进展和 TAM 积累以及表型和遗传特征之间的关系。此外，我们测量了 TNFα、TGFβ、CCL2 和 CXCL12 的血清浓度，并确定了在这种情况下体内 CXCR4/CXCL12 抑制的效果。从脓毒症中存活下来的小鼠在短期和长期都表现出肿瘤进展增加，并且存活时间更短。TAM 积累、TAM 局部增殖以及 TGFβ、CXCL12 和 TNFα 的血清浓度增加。用来自脓毒症后小鼠的巨噬细胞接种 B16 的未感染小鼠也有更快的肿瘤进展和更短的存活时间。脓毒症后 TAMs 的 MHC-II 和白细胞激活相关基因表达减少。CXCR4/CXCL12 的抑制可防止脓毒症引起的肿瘤进展、TAM 积累和 TAM 原位增殖。总的来说，我们的数据表明，脓毒症后状态通过 CXCR4/CXCL12 与 TAM 积累相关，这有助于 B16 黑色素瘤的进展。
