美国加州大学Lawrence Fong团队近期取得重要工作进展，他们研究提出了前列腺癌中骨髓介导的免疫疗法耐药性的演变。相关研究成果2024年12月4日在线发表于《自然》杂志上。

据介绍，晚期转移性抗性前列腺癌患者（mCRPC）对免疫检查点抑制剂（ICI）具有耐药性，部分原因是肿瘤中存在免疫抑制性骨髓细胞。然而，骨髓细胞的异质性使其难以靶向，使得阻断CSF1R在临床上无效。

研究人员对整个疾病连续期的患者活检进行了单细胞分析，发现随着癌症向mCRPC的进展，SPP1转录物（SPP1^hi-TAM）水平升高的肿瘤相关巨噬细胞的不同群体变得丰富。在同基因小鼠模型中，类似的巨噬细胞群在体外抑制CD8⁺ T细胞活性，在体内促进ICI抗性。

此外，Spp1^hi-TAM对抗CSF1R抗体治疗没有反应。通路分析确定腺苷信号传导是SPP1^hi-TAM介导的免疫治疗耐药性的潜在机制。事实上，腺苷A2A受体（A2AR）的药理学抑制在体外显著逆转了Spp1^hi-TAM介导的CD8⁺ T细胞免疫抑制，并在体内增强了CRPC对程序性细胞死亡蛋白1（PD-1）阻断的反应性。与临床前结果一致，使用ciforadenant抑制A2AR联合使用atezolizumab阻断程序性死亡1配体1（PD-L1）可诱导mCRPC患者的临床反应。

此外，抑制A2AR会导致CRPC中SPP1^hi-TAM丰度显著降低，表明该途径参与诱导和下游免疫抑制。总之，这一研究通过腺苷信号传导将SPP1^hi-TAM确立为mCRPC中ICI耐药性的关键介质，强调了它们作为治疗靶点和预测治疗效果的潜在生物标志物的重要性。

附：英文原文

Title: Evolution of myeloid-mediated immunotherapy resistance in prostate cancer

Author: Lyu, Aram, Fan, Zenghua, Clark, Matthew, Lea, Averey, Luong, Diamond, Setayesh, Ali, Starzinski, Alec, Wolters, Rachel, Arias-Badia, Marcel, Allaire, Kate, Wu, Kai, Gurunathan, Vibha, Valderrbano, Laura, Wei, Xiao X., Miller, Richard A., Van Allen, Eliezer M., Fong, Lawrence

Issue&Volume: 2024-12-04

Abstract: Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)1,2, partly because there are immunosuppressive myeloid cells in tumours3,4. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1hi-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8+ T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1hi-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1hi-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1hi-TAM-mediated immunosuppression in CD8+ T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1hi-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1hi-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.

DOI: 10.1038/s41586-024-08290-3

Source: https://www.nature.com/articles/s41586-024-08290-3