Activation of a collaborative innate-adaptive immune response suppresses metastatic breast and ovarian cancer in mice. Activation of a collaborative innate-adaptive immune response suppresses metastatic breast and ovarian cancer in mice

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells, preventing immune control of the cancer. However, macrophages polarized by lipopolysaccharide (a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ) instead kill cancer cells. They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages might therefore be a strategy for controlling tumors. Here, we show that monophosphoryl lipid A (MPLA, a TLR4 agonist used as a vaccine adjuvant)- and IFNγ-activated human macrophages from metastatic breast cancers to kill the same patients’ cancer cells in vitro. Excitingly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also led to reduced metastasis in mouse models of metastatic luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA and IFNγ reprogrammed peritoneal macrophages and suppressed metastasis in ID8-p53-/- ovarian tumor-bearing mice. We found that the combination of MPLA and IFNγ reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, reprogramming tumor-associated (CD206+) macrophages to tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted IL12 and TNFα. Both macrophages and T cells, including memory T cells (CD44+CD62L-), were critical for the anti-metastatic effects of MPLA and IFNγ. MPLA and IFNγ are used individually in humans, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing. Overall design: Expression profile of MMTV-PyMT mammary gland tumor treated with MPLA, IFNg, alone or combined

多种癌症会招募单核细胞/巨噬细胞，并将其极化为肿瘤相关巨噬细胞（Tumor-associated macrophages, TAMs）。肿瘤相关巨噬细胞可促进肿瘤生长与转移，并抑制细胞毒性T细胞，阻碍机体对癌症的免疫调控。然而，经脂多糖（一种细菌来源的Toll样受体4[Toll-like receptor 4, TLR4]激动剂）与干扰素γ（interferon gamma, IFNγ）极化的巨噬细胞却可杀伤癌细胞，其杀伤机制依赖于诱导型一氧化氮合酶（inducible NO synthase, iNOS）生成的一氧化氮（nitric oxide, NO）。因此，调控巨噬细胞的极化状态或许可成为控制肿瘤的治疗策略。本研究证实，单磷酰脂质A（monophosphoryl lipid A, MPLA，一种用作疫苗佐剂的TLR4激动剂）与IFNγ联合激活的转移性乳腺癌患者来源的巨噬细胞，可在体外杀伤同源患者自身的癌细胞。令人振奋的是，在转移性腔面型与三阴性乳腺癌小鼠模型中，瘤内注射MPLA联合IFNγ不仅可抑制局部肿瘤生长，还能减少肿瘤转移。此外，在ID8-p53基因敲除（ID8-p53-/-）卵巢肿瘤荷瘤小鼠中，腹腔给予MPLA与IFNγ可重编程腹膜巨噬细胞，并抑制肿瘤转移。研究发现，MPLA与IFNγ联合治疗可通过以下途径将肿瘤免疫抑制微环境重编程为免疫刺激性微环境：招募白细胞、激活I型干扰素信号通路、将CD206+肿瘤相关巨噬细胞重编程为杀瘤性iNOS+巨噬细胞，以及通过巨噬细胞分泌的白细胞介素12（IL12）与肿瘤坏死因子α（TNFα）激活细胞毒性T细胞。巨噬细胞与T细胞（包括CD44+CD62L-表型的记忆T细胞）均对MPLA与IFNγ的抗转移效应至关重要。MPLA与IFNγ均已单独应用于人体临床治疗，因此本研究提出的无需依赖识别特定肿瘤抗原即可激活抗肿瘤免疫应答的治疗策略，有望在近期投入临床测试。整体实验设计：对分别或联合给予MPLA、IFNγ处理的MMTV-PyMT小鼠乳腺肿瘤进行表达谱分析。