Hofving Tobias, Liang Frank, Karlsson Joakim, Yrlid Ulf, Nilsson Jonas A, Nilsson Ola, Nilsson Lisa M
Sahlgrenska Center for Cancer Research, Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden.
Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden.
Cancers (Basel). 2021 Aug 26;13(17):4305. doi: 10.3390/cancers13174305.
Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
传统上，免疫逃逸和免疫疗法是在黑色素瘤或肺癌等高突变负荷的癌症中进行研究的。相比之下，小肠神经内分泌肿瘤（SINETs）的体细胞突变频率较低，被描述为基因稳定的肿瘤，这使得免疫疗法对SINET患者来说在很大程度上仍是未知领域。SINETs在诊断时经常转移至区域淋巴结和肝脏，目前对于播散性疾病患者尚无治愈性治疗方法。在此，我们对SINET的免疫格局进行了表征，并证明在自体肿瘤攻击过程中肿瘤浸润淋巴细胞（TILs）可被扩增和激活。通过对一例肝转移和六例淋巴结转移的SINET微环境进行免疫表型分析，确定了淋巴细胞亚群的组成。从这些转移灶中成功培养出TILs，从而能够进行免疫表型分析和PD-1表达评估。TILs的扩增以及在体外与自体肿瘤细胞接触导致T淋巴细胞脱颗粒增加。本研究为很大程度上未知的SINET免疫格局提供了见解，并揭示了TILs的抗肿瘤反应性，这可能使过继性T细胞转移成为SINET患者可行的治疗选择。
