Department of Innate Immunity, Indian Council of Medical Research (ICMR)- National Institute for Research in Reproductive and Child Health, Mumbai, India.
Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.
Front Immunol. 2022 Jul 7;13:930449. doi: 10.3389/fimmu.2022.930449. eCollection 2022.
Surfactant protein D (SP-D), a pattern recognition molecule, is emerging as a potent anti-tumoural innate immune defense molecule in a range of cancers. Previously, SP-D expression was found to be significantly downregulated at the malignant sites of human prostate adenocarcinoma and associated with an increasing Gleason score and severity. We recently reported selective induction of intrinsic apoptosis by a recombinant fragment of human SP-D (rfhSP-D) in the human Prostate cancer (PCa) biopsy explants and cells with glucose regulated protein of 78 (GRP78) as one of the key interacting partners. The present study evaluated the expression of SP-D in early and advanced stages of PCa using transgenic adenocarcinoma of mouse prostate (TRAMP) model. Both early and late stages of PCa showed significantly decreased SP-D mRNA expression and increased proteolytic degradation of SP-D protein. Systemic and tumoural immunophenotyping of TRAMP model revealed increased serine proteases producing granulocytes and polymorphonuclear myeloid-derived suppressor cells (PMN MDSCs) in the late stage; the serine proteases secreted by these cells could be involved in the degradation of SP-D. Susceptibility of rfhSP-D to elastase-mediated proteolysis provided the rationale to use an elastase-inhibitor to sustain intact rfhSP-D in the tumour microenvironment. The study revealed an immunomodulatory potential of rfhSP-D and elastase inhibitor, sivelestat, to induce macrophage polarization towards M1 with downregulation of PMN MDSCs in cultured TRAMP tumours. Furthermore, rfhSP-D induced immunogenic cell death in murine PCa cells and in TRAMP explants. The findings highlight that SP-D plays an anti-tumourigenic role in PCa by inducing immunogenic cell death and immunomodulation while the prostate tumour milieu adversely impacts SP-D by inhibiting its transcription, and enhancing its proteolytic degradation. Transformation of an immunologically "cold tumour" into a "hot tumour" implicates therapeutic potential of rfhSP-D in PCa.
表面活性蛋白 D（SP-D）是一种模式识别分子，作为一种有效的抗肿瘤先天免疫防御分子，在多种癌症中逐渐显现。此前发现，人前列腺腺癌恶性部位 SP-D 的表达显著下调，且与 Gleason 评分和严重程度的增加相关。我们最近报道了重组人 SP-D（rfhSP-D）片段在人前列腺癌（PCa）活检标本和葡萄糖调节蛋白 78（GRP78）作为关键相互作用伙伴之一的 PCa 细胞中选择性诱导内在凋亡。本研究使用转基因前列腺癌小鼠模型（TRAMP）评估了 PCa 早期和晚期 SP-D 的表达。PCa 的早期和晚期均显示 SP-DmRNA 表达显著降低，SP-D 蛋白的蛋白水解降解增加。TRAMP 模型的系统性和肿瘤免疫表型分析显示，晚期粒细胞和多形核髓源抑制细胞（PMN MDSCs）中产生丝氨酸蛋白酶的数量增加；这些细胞分泌的丝氨酸蛋白酶可能参与了 SP-D 的降解。rfhSP-D 易受弹性蛋白酶介导的蛋白水解作用，这为使用弹性蛋白酶抑制剂在肿瘤微环境中维持完整的 rfhSP-D 提供了依据。该研究揭示了 rfhSP-D 和弹性蛋白酶抑制剂西维来司他具有免疫调节潜力，可诱导巨噬细胞向 M1 极化，并下调培养的 TRAMP 肿瘤中的 PMN MDSCs。此外，rfhSP-D 诱导了小鼠 PCa 细胞和 TRAMP 外植体中的免疫原性细胞死亡。这些发现强调了 SP-D 通过诱导免疫原性细胞死亡和免疫调节在 PCa 中发挥抗肿瘤作用，而前列腺肿瘤微环境通过抑制其转录和增强其蛋白水解降解来对 SP-D 产生不利影响。将免疫“冷肿瘤”转化为“热肿瘤”提示 rfhSP-D 在 PCa 中的治疗潜力。
