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Identification of an immune overdrive high-risk subpopulation with aberrant expression of FOXP3 and CTLA4 in colorectal cancer

Abstract

Colorectal cancer (CRC) is characterized by a heterogeneous tumor microenvironment (TME) that regulates cancer progression and therapeutic response. Overexpression of FOXP3 and CTLA4 is associated with immunosuppressive TME and poor prognosis in many cancer types. However, opposite results were reported in CRC. Thus, we performed comprehensive analyses to evaluate the exact prognostic value of FOXP3 and CTLA4 in CRC. Here, the expression levels of FOXP3 and CTLA4 were used to construct a subtyping system based on >1200 CRC patients from multiple independent public datasets. We revealed that, in CRC patients with relatively high expression of FOXP3, there exist two different subpopulations with opposite survival patterns according to CLTA4 expression. We further established a method for evaluating all cohorts and identified a novel FOXP3HighCTLA4High* CRC risk subpopulation that accounts for 5–10% of CRC patients. Moreover, different methods of functional enrichment and immune evaluation were used to analyze the TME characteristics of different FOXP3/CTLA4 subtypes. The FOXP3HighCTLA4High* CRC risk subpopulation was characterized by an immune overdrive TME phenotype, including high immune cell infiltration, low tumor purity, high immune checkpoint levels, and TGF-β activation. Finally, the constructed FOXP3/CTLA4 subtyping system was further validated by quantitative RT-PCR, immunochemistry staining, and multicolor immunofluorescence in an independent CRC cohort we collected. This high-risk subpopulation was also observed in kidney cancers and low-grade glioma patients by a Pan-cancer analysis. Together, our study revealed that the established FOXP3/CTLA4 molecular subtyping system could be used to select treatment and management strategies for CRC and other cancers.

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Fig. 1: Two subpopulations with high CTLA4 expression show opposite 5-year OS in FOXP3-overexpressing CRC patients.
Fig. 2: The prognostic value of CTLA4 is dependent on FOXP3 expression in CRC.
Fig. 3: FOXP3HighCTLA4High* patients represent a novel high-risk subpopulation in CRC.
Fig. 4: Immune characteristics of the FOXP3HighCTLA4High* risk subpopulation.
Fig. 5: Molecular subtypes characteristics of the FOXP3HighCTLA4High* risk subpopulation.
Fig. 6: Independent validation of the FOXP3/CTLA4 subtyping system in Asian validation cohorts.
Fig. 7: Pan-cancer prognostic significance of FOXP3HighCTLA4High* subpopulation.
Fig. 8

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Acknowledgements

We thank the TCGA, GEO, and CPTAC project. We thank the Affiliated Hospital of Jiangnan University for providing the CRC samples. This work was supported by grants from the National Natural Science Foundation of China (82002550, 81672328, and 81972220), Jiangsu Key Research and Development Plan (BE2019632), Medical Key Professionals Program of Jiangsu Province (AF052141), National First-class Discipline Program of Food Science and Technology (JUFSTR20180101), and Wuxi Medical Innovation Team (CXTP003).

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Correspondence to Zhaohui Huang.

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Cui, K., Yao, S., Zhang, H. et al. Identification of an immune overdrive high-risk subpopulation with aberrant expression of FOXP3 and CTLA4 in colorectal cancer. Oncogene 40, 2130–2145 (2021). https://doi.org/10.1038/s41388-021-01677-w

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