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PIK3CA mutation-induced immune microenvironment remodeling sensitizes cervical cancer to immunotherapy
Fei Zhu1, Xingyun Xie1, Cong Wang2
1Departments of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
Abstract:
PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8+ T-cell exhaustion through both canonical PD-L1-PD-1 signaling and the non-canonical SPP1-CD44 axis. Additionally, PIK3CA mutations enrich for MMP9+ macrophages that promote tumor angiogenesis through ANGPTL4 signaling. This dual landscape of T-cell exhaustion and active angiogenesis provides a framework for the observed synergy between PD-1 blockade and anti-angiogenic therapies. The findings demonstrate that the presence of PIK3CA mutations is a key predictive biomarker for guiding combination immunotherapy in CC and identify a rational basis for co-targeting distinct immune and vascular resistance pathways.
Insights
PIK3CA mutations in cervical cancer create a complex tumor microenvironment (TME) with T-cell inflammation and immune resistance. This finding highlights PIK3CA as a biomarker for combination immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- PIK3CA mutations are common in cervical cancer (CC) but have unclear clinical utility due to paradoxical treatment outcomes.
- Precision oncology efforts are limited by the complex role of PIK3CA in CC.
Purpose of the Study:
- To construct a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment (TME).
- To investigate how PIK3CA mutations influence the TME and immune responses in CC.
- To identify potential therapeutic strategies targeting PIK3CA-mutated CC.
Main Methods:
- Single-cell RNA sequencing to create a transcriptomic atlas of the CC TME.
- Analysis of gene expression patterns and cellular interactions within the TME.
- Investigating signaling pathways involved in T-cell exhaustion and angiogenesis.
Main Results:
- PIK3CA mutations induce a dichotomous TME characterized by T-cell inflammation and adaptive immune resistance.
- Malignant epithelial cells promote CD8+ T-cell exhaustion via PD-L1/PD-1 and SPP1/CD44 pathways.
- PIK3CA mutations enrich MMP9+ macrophages, driving tumor angiogenesis through ANGPTL4 signaling.
Conclusions:
- PIK3CA mutations are a predictive biomarker for guiding combination immunotherapy in CC.
- The study identifies a rationale for co-targeting immune and vascular resistance pathways in PIK3CA-mutated CC.
- Targeting both T-cell exhaustion and angiogenesis may overcome resistance to current therapies.
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