UCL Cancer Institute, UCL, London, United Kingdom.
Cancer Immunology Unit, Research Department of Hematology, UCL Cancer Institute, UCL, London, United Kingdom.
Clin Cancer Res. 2022 Jun 13;28(12):2657-2668. doi: 10.1158/1078-0432.CCR-21-4203.
The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined.
Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration.
Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an "exclusion" phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio.
Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit "excluded" T cells into the tumor microenvironment to treat patients with siNETs.
小肠神经内分泌肿瘤（siNET）的肿瘤免疫微环境以及免疫疗法的潜在治疗机会尚未完全明确。
在此，我们研究了 40 例原发性和同步转移性 siNET 患者，并在手术期间匹配获得了血液和正常组织。我们使用多参数流式细胞术研究了免疫检查点景观。此外，还获得了匹配的 FFPE 组织，以进行多参数免疫组化（IHC），以确定 T 细胞浸润的相对丰度和分布。还评估了肿瘤突变负担（TMB），并将其与免疫浸润相关联。
效应性肿瘤浸润淋巴细胞（TIL）在肿瘤微环境中的 PD-1 表达高于外周血。此外，CD8+TIL 具有更高的 PD-1/ICOS 和 PD-1/CTLA-4（细胞毒性 T 淋巴细胞抗原-4）共表达以及更高的 PD-1 表达水平，与正常组织相比。IHC 显示，大多数病例的肿瘤内 T 细胞数≤10％，但肿瘤周围的 T 细胞数更多，表现出“排斥”表型。最后，我们证实，与 TCGA 数据库中的其他肿瘤类型相比，siNET 的 TMB 较低，但未发现 TMB 与 CD8/Treg 比值之间存在相关性。
综上所述，这些结果表明，将需要联合治疗方法来增强免疫反应，将 PD-1 作为检查点免疫调节剂的骨干，与其他检查点靶向分子（CTLA-4 或 ICOS）联合使用，或与靶向其他途径的药物联合使用，以将“排斥”的 T 细胞招募到肿瘤微环境中，从而治疗 siNET 患者。
