2. Academic Validation
  3. FOSL2 promotes intertumoral infiltration of T cells and increases pathological complete response rates in locally advanced rectal cancer patients

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

  • Cancer Lett. 2023 Mar 28;216145. doi: 10.1016/j.canlet.2023.216145.
Kailun Xu 1,  Xiaoyang Yin 2,  Biting Zhou 3,  Xi Zheng 4,  Hao Wang 5,  Jing Chen 6,  Xue Cai 7,  Huanhuan Gao 8,  Xiaoming Xu 9,  Liuhong Wang 10,  Li Shen 11,  Tiannan Guo 12,  Shu Zheng 13,  Baosheng Li 14,  Yingkuan Shao 15,  Jian Wang 16
Affiliations

Affiliations

  • 1 Department of Breast Surgery and Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China. Electronic address: xukailun@zju.edu.cn.
  • 2 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. Electronic address: xiaoyangy2019@163.com.
  • 3 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: zhoubiting@zju.edu.cn.
  • 4 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: zhengxisue@zju.edu.cn.
  • 5 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: 22118537@zju.edu.cn.
  • 6 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: shiqi0611@163.com.
  • 7 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Research Center for Industries of the Future, Center for Infectious Disease Research, Westlake University, Hangzhou, 310024, Zhejiang Province, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China. Electronic address: caixue@westlake.edu.cn.
  • 8 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Research Center for Industries of the Future, Center for Infectious Disease Research, Westlake University, Hangzhou, 310024, Zhejiang Province, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China. Electronic address: gaohuanhuan@westlake.edu.cn.
  • 9 Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. Electronic address: xu2008711@zju.edu.cn.
  • 10 Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. Electronic address: wlh20020905@163.com.
  • 11 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: sl_hz@163.com.
  • 12 Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Research Center for Industries of the Future, Center for Infectious Disease Research, Westlake University, Hangzhou, 310024, Zhejiang Province, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China. Electronic address: guotiannan@westlake.edu.cn.
  • 13 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Radiation Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: zhengshu@zju.edu.cn.
  • 14 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. Electronic address: bsli@sdfmu.edu.cn.
  • 15 Department of Breast Surgery and Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China. Electronic address: ykshao@zju.edu.cn.
  • 16 Zhejiang Provincial Clinical Research Center for Cancer, China; Cancer Center of Zhejiang University, China; Department of Colorectal Surgery and Oncology, (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: wangjian519@zju.edu.cn.
PMID: 36997107 DOI: 10.1016/j.canlet.2023.216145
Abstract

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-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.

Keywords

FOSL2; Immune infiltration; Locally advanced rectal cancer; Neoadjuvant chemoradiotherapy; Pathological complete response.

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