Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-006433.
Primary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome.
Here, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied. Exploration of the tumor microenvironment by high dimensional flow cytometry in combination with therapeutic settings allowed for the identification of immunological factors driving immunotherapy resistance.
Comparison of the tumor immune infiltrate during early and late regression revealed a change from tumor-rejecting toward tumor-promoting macrophages. In concert, a rapid exhaustion of tumor-infiltrating T cells was observed. Perturbation studies identified a small but discernible CD163 macrophage population, with high expression of several tumor-promoting macrophage markers and a functional anti-inflammatory transcriptome profile, but not other macrophages, to be responsible. In-depth analyses revealed that they localize at the tumor invasive margins and are more resistant to Csf1r inhibition when compared with other macrophages. studies validated the activity of heme oxygenase-1 as an underlying mechanism of immunotherapy resistance. The transcriptomic profile of CD163 macrophages is highly similar to a human monocyte/macrophage population, indicating that they represent a target to improve immunotherapy efficacy.
In this study, a small population of CD163 tissue-resident macrophages is identified to be responsible for primary and secondary resistance against T-cell-based immunotherapies. While these CD163 M2 macrophages are resistant to Csf1r-targeted therapies, in-depth characterization and identification of the underlying mechanisms driving immunotherapy resistance allows the specific targeting of this subset of macrophages, thereby creating new opportunities for therapeutic intervention with the aim to overcome immunotherapy resistance.
原发性和继发性耐药是癌症免疫治疗的主要障碍。因此，更好地了解免疫治疗耐药相关的潜在机制对于改善治疗效果至关重要。
本研究中，我们研究了两种对治疗性疫苗诱导的肿瘤消退产生耐药的小鼠模型。通过高维流式细胞术结合治疗方案探索肿瘤微环境，有助于鉴定驱动免疫治疗耐药的免疫学因素。
早期和晚期消退过程中肿瘤免疫浸润的比较显示，肿瘤排斥性向肿瘤促进性巨噬细胞发生转变。同时，观察到肿瘤浸润 T 细胞迅速耗竭。扰动研究确定了一小部分但可识别的 CD163 巨噬细胞群，其具有高表达几种促进肿瘤的巨噬细胞标志物和功能上抗炎的转录组谱，但不是其他巨噬细胞，具有这种功能。深入分析表明，它们定位于肿瘤浸润边缘，并且与其他巨噬细胞相比，对 CSF1R 抑制的抵抗力更强。研究验证了血红素加氧酶-1 作为免疫治疗耐药的潜在机制。CD163 巨噬细胞的转录组谱与人类单核细胞/巨噬细胞群高度相似，表明它们是改善免疫治疗疗效的靶点。
在这项研究中，确定了一小群 CD163 组织驻留巨噬细胞负责 T 细胞为基础的免疫疗法的原发性和继发性耐药。虽然这些 CD163 M2 巨噬细胞对 CSF1R 靶向治疗具有耐药性，但对驱动免疫治疗耐药的潜在机制的深入表征和鉴定允许针对该巨噬细胞亚群进行特异性靶向，从而为克服免疫治疗耐药创造新的治疗干预机会。
