Tsunokake Junichi, Fujishima Fumiyoshi, Watanabe Hirofumi, Sato Ikuro, Miura Koh, Sakamoto Kazuhiro, Suzuki Hiroyoshi, Sawai Takashi, Itakura Yuko, Hoshi Tatsuya, Kunimitsu Atsushi, Yamauchi Takuro, Akaishi Ryujiro, Ozawa Yohei, Fukutomi Toshiaki, Okamoto Hiroshi, Sato Chiaki, Taniyama Yusuke, Kamei Takashi, Sasano Hironobu
Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Cancers (Basel). 2022 Apr 26;14(9):2152. doi: 10.3390/cancers14092152.
The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.
肿瘤微环境被认为在各种人类恶性肿瘤中起关键作用。神经内分泌肿瘤和非神经内分泌肿瘤被认为具有不同的肿瘤微环境。然而，由于全身和/或局部免疫状态的差异，不同患者的肿瘤微环境可能难以比较。混合性神经内分泌-非神经内分泌肿瘤（MiNENs）虽然罕见，但可能有助于探索神经内分泌分化对肿瘤微环境的影响，因为同一肿瘤中同时存在神经内分泌和非神经内分泌成分。在此，我们检查了33例组织学确诊的MiNENs，并通过比较同一肿瘤中两个成分的肿瘤浸润淋巴细胞、肿瘤相关巨噬细胞及其他相关因素，评估神经内分泌分化对肿瘤微环境的影响。对上述检测指标的免疫反应性进行定量评估。与同一肿瘤的非神经内分泌区域相比，神经内分泌区域的血管抑制素-1阳性密度（p < 0.0001）和免疫反应性（p < 0.0001）（代表新生血管形成状态）显著更高。此外，神经内分泌癌中Foxp3/CD8（p = 0.0717）和PD-1/CD8比值（p = 0.0176）（代表肿瘤免疫抑制）有升高趋势。M2样巨噬细胞标志物CD163的免疫反应性在神经内分泌区域也更高。我们的研究结果表明，神经内分泌肿瘤和非神经内分泌肿瘤在肿瘤细胞及肿瘤微环境特征方面彼此不同。
