Low Necroptosis Process Predicts Poor Treatment Outcome of Human Papillomavirus Positive Cervical Cancers by Decreasing Tumor-Associated Macrophages M1 Polarization

Abstract

Background/Aim: The aim of this study was to assess the functions of the necroptosis process on the prognosis of high-risk human papillomavirus (HR-HPV)-related cervical cancer. Methods: PCR and western blotting were used to demonstrate the expression of the necroptosis marker, mixed lineage kinase domain-like protein (MLKL), in whole blood and peripheral blood mononuclears (PBMCs) of 89 cervical cancer patients and 15 healthy volunteers. Necroptosis levels and M1 polarization were determined in tumor co-cultured macrophages. Results: We found that MLKL expressions were significantly increased in cervical cancer patients in both whole blood and PBMC samples compared to the expressions in the healthy controls. Low MLKL expression was significantly associated with decreased survival rate in overall survival and disease-free survival. Co-culture cervical cancer cells decrease the necroptosis process of macrophage, together with the proinflammatory factors (M1 markers) downregulation, and this negative regulation was exacerbated in HPV-positive cases. Necroptosis enhancer RIPK3 overexpression showed reversed regulation of these M1 markers, suggesting that co-culture cervical cancer cells decrease the macrophage M1 polarization partly through necroptosis downregulation. Conclusion: Our study revealed that necroptosis process could be a relevant marker for the determination of the prognosis in cervical cancer patients, which might be because of its role in regulating macrophage polarization.

Comparing the effects of different cell death programs in tumor progression and immunotherapy

“…Additionally, RIPK3 mRNA is decreased in human colorectal cancer (CRC) tissues compared to healthy colon controls [75], and loss of RIPK3 is associated with tumor progression in CRC [76]. Conversely, increased expression of RIPK3 positively correlates with favorable outcomes in a variety of human tumors, including HPV + cervical cancer [77] and AML [78]. Consistent with the idea that RIPK3 expression promotes antitumor responses, the locus of the RIPK3 gene (chromosome 14q11.2) [79] is frequently mutated in several types of neoplasia, including nasopharyngeal carcinoma [80] and acute lymphoblastic leukemia [81], although it remains to be determined whether these mutations are specifically within the RIPK3 gene.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…Decreased overall survival and disease-free survival [229] Ovarian cancer Decreased overall survival. [230] Pancreatic adenocarcinoma…”

The Formation and Therapeutic Update of Tumor-Associated Macrophages in Cervical Cancer

“…It was further discovered that when treated with the supernatant of CC cell lines, M1-like macrophages developed an M2-like phenotype with increased CD163, TLR-3, -7, -9 and IL-10 [25,26]. Similarly, co-culture cervical cancer cells decrease the macrophage M1-like polarization partly through necroptosis downregulation [27]. However, these studies did not clarify which component of the supernatant was responsible for the M2-like induction.…”

“…These studies showed TAMs in CC have a M2-like phenotype because most infiltrating and pro-tumor macrophages were M2-like. M1-like macrophages existed in the CC tumor stroma with a declined expression of M1-like markers such as IL-6, TNF-α and iNOS and tendedto transfer to M2-like phenotype under the influence of tumor cells [27]. Other markers of M1-like were also used in CC research such as CD163- [25,89], CD163+ pSTAT1 [90], IL-12p40 [27], CD80+ [26], HLA-DR [26] and CXCL10 [35].…”

“…M1-like macrophages existed in the CC tumor stroma with a declined expression of M1-like markers such as IL-6, TNF-α and iNOS and tendedto transfer to M2-like phenotype under the influence of tumor cells [27]. Other markers of M1-like were also used in CC research such as CD163- [25,89], CD163+ pSTAT1 [90], IL-12p40 [27], CD80+ [26], HLA-DR [26] and CXCL10 [35]. The most common marker for M2 is CD163+ [25,26,35,73,78,89,91,92,93,94,95,96,97].…”