FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients

• Published in: Cancer letters 2023-05, Vol.562, p.216145-216145, Article 216145
• Main Authors: Xu, Kailun, Yin, Xiaoyang, Zhou, Biting, Zheng, Xi, Wang, Hao, Chen, Jing, Cai, Xue, Gao, Huanhuan, Xu, Xiaoming, Wang, Liuhong, Shen, Li, Guo, Tiannan, Zheng, Shu, Li, Baosheng, Shao, Yingkuan, Wang, Jian
• Format: Article
• Language: English
• Subjects: Chemoradiotherapy - methods; Disease-Free Survival; Fos-Related Antigen-2; FOSL2; Humans; Immune infiltration; Locally advanced rectal cancer; Neoadjuvant chemoradiotherapy; Neoadjuvant Therapy - methods; Pathological complete response; Proteomics; Rectal Neoplasms - genetics; Rectal Neoplasms - therapy; Treatment Outcome
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216145

The outcome of neoadjuvant chemoradiotherapy (nCRT) remains highly unpredictable for individuals with locally advanced rectal cancer (LARC). We set out to characterize effective biomarkers that promote a pathological complete response (pCR). We quantified the abundances of 6483 high-confidence proteins in pre-nCRT biopsies of 58 LARC patients from two hospitals with pressure cycling technology (PCT)-assisted pulse data-independent acquisition (PulseDIA) mass spectrometry. Compared with non-pCR patients, pCR patients achieved long-term disease-free survival (DFS) and had higher tumor immune infiltration, especially CD8+ T cell infiltration, before nCRT. FOSL2 was selected as the candidate biomarker for predicting pCR and was found to be significantly upregulated in pCR patients, which was verified in another 54 pre-nCRT biopsies of LARC patients by immunohistochemistry. FOSL2 expression was able to predict pCR by multiple reaction monitoring (MRM) with high efficiency (Area under curve (AUC) = 0.939, specificity = 1.000, sensitivity = 0.850), and high FOSL2 expression was associated with long-term DFS (p = 0.044). When treated with simulated nCRT, FOSL2 sufficiency resulted in more significant inhibition of cell proliferation, and more significant promotion of cell cycle arrest and cell apoptosis. Moreover, CXCL10 secretion with abnormal cytosolic dsDNA accumulation was found in FOSL2-wildtype (FOSL2-WT) tumor cells over nCRT, which might elevate CD8+ T-cell infiltration and CD8+ T-cell-mediated cytotoxicity to promote nCRT-induced antitumor immunity. Our study revealed proteomic profiles in LARC patients before nCRT and highlighted immune activation in the tumors of patients who achieved pCR. We identified FOSL2 as a promising biomarker to predict pCR and promote long-term DFS by contributing to CD8+ T-cell infiltration. •pCR patients achieved a long-term DFS and had higher immune infiltration in the tumor before nCRT, especially CD8+ T cells.•FOSL2 was significantly up-regulated in pCR patients and identified to predict pCR by PulseDIA and MRM.•FOSL2 elevated CD8+T cell infiltration and CD8+T cell-mediated cytotoxicity after nCRT.•In the tumor cells with FOSL2 expression, more CXCL10 secretion with cytosolic dsDNA abnormal accumulation over nCRT.