采用联合免疫疗法治疗鼻窦未分化癌。

Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach.

作者信息

Hoke Austin T K, Takahashi Yoko, Padget Michelle R, Gomez Javier, Amit Moran, Burks Jared, Bell Diana, Xie Tongxin, Soon-Shiong Patrick, Hodge James W, Hanna Ehab Y, London Nyall R

机构信息

Sinonasal and Skull Base Tumor Program, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, United States.

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

出版信息

Transl Oncol. 2024 Jun;44:101943. doi: 10.1016/j.tranon.2024.101943. Epub 2024 Apr 10.

DOI:10.1016/j.tranon.2024.101943

PMID:38593586

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11024348/

Abstract

PURPOSE

Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME).

EXPERIMENTAL DESIGN

Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed.

RESULTS

Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines ∼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1 tumor cells at a median of 5.4 cells per mm. A striking 55.7-fold increase in CK tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3CD8 in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CK tumor cell/CD8 cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225).

CONCLUSION

These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.

摘要

目的

鼻窦未分化癌（SNUC）是一种罕见的鼻窦侵袭性恶性肿瘤，预后较差且治疗选择有限。为了研究SNUC对联合免疫疗法的敏感性，我们使用SNUC细胞系进行了体外研究，并采用多光谱免疫荧光法对患者体内的SNUC肿瘤免疫微环境（TIME）进行了表征。

实验设计

用人源SNUC细胞系对基于自然杀伤（NK）细胞的免疫治疗策略的肿瘤细胞敏感性进行体外研究。通过多光谱免疫荧光检查14例未经治疗的SNUC患者的肿瘤样本，并评估临床相关性。

结果

抗PD-L1阻断使SNUC细胞系的NK细胞裂解增强约5.4倍（P≤0.0001）。这种效应被CD16中和抗体阻断，表明其通过抗体依赖性细胞毒性（ADCC）介导的途径发挥活性。通过外源性干扰素-γ（IFN-γ）给药使肿瘤细胞上的PD-L1上调或白细胞介素-15（IL-15）刺激NK细胞释放IFN-γ，可进一步增强SNUC细胞的ADCC依赖性裂解。抗PD-L1阻断与IL-15超激动剂联合治疗使NK细胞对SNUC细胞的杀伤增强9.6倍（P≤0.0001）。未经治疗的SNUC患者肿瘤样本中，NK细胞浸润和PD-L1肿瘤细胞的中位数为每平方毫米5.4个细胞。在治疗后无疾病复发的患者中，观察到细胞角蛋白（CK）肿瘤细胞/NK细胞相互作用显著增加55.7倍（P = 0.022）。基质中CD3CD8较高的患者5年总生存率显著提高（P = 0.0029），长期存活者中CK肿瘤细胞/CD8细胞毒性T细胞相互作用显著增加（P = 0.0225）。