Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
J Hematol Oncol. 2021 Sep 8;14(1):142. doi: 10.1186/s13045-021-01156-5.
Tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb.
We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2IL-2R-γc-KO (BRG) mice. Depleting antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, was tested for its effect on TIMs.
BsAb-driven T cells recruited myeloid cells into human tumor xenografts. Each TIM targeting therapy depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, and particularly TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and survival in multiple cancer xenograft models. Dexamethasone premedication depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and anti-tumor response with survival benefit.
Reducing TIMs markedly enhanced anti-tumor effects of BsAb-based T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion was more effective than PMN- or M-MDSCs depletion at boosting the anti-tumor response of T cell engaging BsAb.
肿瘤微环境（TME）是一种动态的细胞环境，可促进肿瘤血管生成、生长、增殖和转移，同时破坏宿主的抗肿瘤反应。TME 阻碍了双特异性抗体（BsAb）或嵌合抗原受体（CAR）驱动的 T 细胞浸润、存活和细胞毒性疗效。调节肿瘤浸润髓样细胞（TIMs）可能会提高 BsAb 的疗效。
我们评估了 TIM 调节对 BsAb 驱动的 T 细胞浸润肿瘤、其持久性和体内抗肿瘤反应的影响。基于 IgG-[L]-scFv 平台构建的抗-GD2 BsAb 和抗-HER2 BsAb 在 BALB-Rag2IL-2R-γc-KO（BRG）小鼠中针对人源肿瘤异种移植物进行了测试。使用针对多形核髓样来源抑制细胞（PMN-MDSC）、单核细胞 MDSC（M-MDSC）和肿瘤相关巨噬细胞（TAM）的特异性耗竭抗体来研究每个 TIM 成分的作用。地塞米松是一种已确立的抗炎剂，用于测试其对 TIMs 的影响。
BsAb 驱动的 T 细胞将髓样细胞募集到人源肿瘤异种移植物中。每种 TIM 靶向治疗都在血液和肿瘤中耗竭了感兴趣的细胞。PMN-MDSC、M-MDSC 的耗竭，特别是 TAM 的耗竭，与 T 细胞更有效地浸润肿瘤相关，显著改善了多种癌症异种移植模型中的肿瘤控制和生存。地塞米松预处理耗竭了循环中的单核细胞和肿瘤中的 TAMs，增强了 BsAb 驱动的 T 细胞浸润和抗肿瘤反应，并带来了生存获益。
通过改善肿瘤内 T 细胞浸润和持久性，减少 TIMs 显著增强了基于 BsAb 的 T 细胞免疫疗法的抗肿瘤效果。与耗竭 PMN- 或 M-MDSC 相比，TAM 耗竭在增强 T 细胞结合 BsAb 的抗肿瘤反应方面更有效。
