肿瘤相关巨噬细胞诱导免疫抑制微环境促进乳腺癌内分泌耐药

Endocrine resistance is an important issue to be solved in the breast cancer field. TAMs can promote breast cancer cells to generate endocrine resistance. Previous studies found that the effect of endocrine therapy in breast cancer was negatively correlated with TAMs and Treg infiltration into tumor tissue. We used multiplex bioassay to detect TAMs in the tissue of drug-resistant patients and found the expression of CXCL3, IL-13, IL-6, and other genes was significantly increased, preliminarily confirming TAMs influence Treg and iDCs generation, and PD-1 monoclonal antibody can restore tumor sensitivity to endocrine drugs. Through in vivo and in vitro experiments, as well as clinical samples, this study will validate that TAMs promote Treg and iDCs generation, induce PD-L1 / PD-1 expression, and exacerbate endocrine resistance. The study will focus on the key factors that can continuously amplify immunosuppressive effects in the TAMs/Treg/iDCs loop, as well as the primary signaling pathways for TAMs to induce immunosuppressive endocrine microenvironment and promote drug resistance, and determine the mechanisms by which PD-1 monoclonal antibody remodels immune microenvironment and reverse drug resistance. The study is expected to find a novel mechanism by which the immunosuppressive microenvironment promotes endocrine resistance, and that PD-1 monoclonal antibody combined with mTOR inhibitors may reverse drug resistance to a greater extent, providing the basis for reshaping the immune microenvironment to reverse endocrine resistance.

内分泌耐药是乳腺癌领域亟待解决的重要问题，肿瘤相关巨噬细胞（TAMs）可促使乳腺癌细胞产生内分泌耐药。前期研究发现内分泌治疗效果与肿瘤组织TAMs、Treg浸润负相关；我们利用芯片技术检测了耐药患者组织中TAMs细胞因子、趋化因子表达，发现CXCL3、IL-6及IL-13等表达明显升高，初步证实TAMs对Treg、iDCs生成有影响；PD-1单抗能恢复肿瘤对内分泌药物的敏感性。本研究拟通过体内外实验和临床标本验证：TAMs可通过促进Treg、iDCs生成，诱导PD-L1/PD-1表达，加剧内分泌耐药；重点研究TAMs诱导免疫抑制微环境的关键因子及其促进内分泌耐药的主要通路；明确PD-1单抗重塑免疫微环境逆转耐药的机制。本研究有望发现免疫抑制微环境促进内分泌耐药的新机制，PD-1单抗与mTOR抑制剂联用可更大程度地逆转耐药，为重塑免疫微环境逆转内分泌耐药提供依据。

内分泌耐药是乳腺癌领域亟待解决的重要问题，肿瘤相关巨噬细胞（TAMs）可促使乳腺癌细胞产生内分泌耐药。本研究从检测内分泌耐药患者TAMs的细胞因子、趋化因子表达差异发现入手，发现CXCL3、IL-6及IL-13等表达明显升高，初步证实TAMs对Treg、iDCs生成有影响；通过体内外及临床研究，我们证实TAMs可通过促进Treg、iDCs生成等途径，加剧内分泌耐药；PD-1单抗与mTOR抑制剂联用可更大程度地逆转耐药。本研究提供了免疫抑制微环境促进内分泌耐药的新机制，为重塑免疫微环境逆转内分泌耐药提供依据。