Regulatory T cells poise the myeloid landscape after chemotherapy in lung tumors

Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. While Tregs are well known for their immune suppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. We showed in human and mouse lung cancer, that chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward a pro-inflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the pro-inflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the pro-inflammatory signature of the MPs and improved survival in the mouse model. Targeting the crosstalk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome. Four sorted tumor samples, each pooled from three mice with multifocal lung tumors, were analyzed: untreated (NT), chemotherapy-treated (CP), chemotherapy plus anti-TNFR2-treated (CP_aTNFRII) and local irradiation (IR). The samples include T lymphocyte and myeloid cell populations, analyzed using scRNA-seq.

肿瘤相关巨噬细胞（Tumor-associated macrophages, TAMs）与调节性T细胞（regulatory T cells, Tregs）是肿瘤微环境的核心免疫组分，在几乎所有癌症适应证中均可促进肿瘤生长并抑制化疗疗效。尽管Tregs对适应性免疫系统的免疫抑制活性已被广泛认知，但其对先天免疫区室的调控作用却鲜有研究。本研究在人类及小鼠肺癌模型中证实，化疗可短暂降低Tregs数量，使单核吞噬细胞（mononuclear phagocyte, MP）群体向促炎表型转变，但随着时间推移，表达转化生长因子β（TGFβ）的TAMs的积累也会增加。抑制Tregs的恢复可进一步增强单核细胞招募，并在TAM分化过程中限制TGFβ的表达，这表明Tregs会削弱化疗诱导的MP区室的促炎状态，并促进肿瘤复发。在Tregs恢复阶段给予抗TNFR2抗体治疗，可影响Tregs与MPs之间的直接相互作用，增强MPs的促炎特征，并改善小鼠模型的生存率。靶向肿瘤相关Tregs与MP区室之间的串扰，可限制化疗后抗炎环境的重建，并改善治疗结局。本研究共分析4份分选后的肿瘤样本，每份样本均由3只患有多灶性肺癌的小鼠的肿瘤组织混合而成：未处理组（untreated, NT）、化疗组（chemotherapy-treated, CP）、化疗联合抗TNFR2治疗组（chemotherapy plus anti-TNFR2-treated, CP_aTNFRII）以及局部照射组（local irradiation, IR）。所有样本均涵盖T淋巴细胞与髓系细胞群体，并采用单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）进行分析。