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Translational Therapeutics

Stratifying ICIs-responsive tumor microenvironment in HCC: from parsing out immune-hypoxic crosstalk to clinically applicable MRI-radiomics models

British Journal of Cancer volume 130, pages 1356–1364 (2024)Cite this article

Subjects

Abstract

Background

We aimed to redefine Immune checkpoint inhibitors (ICIs)-responsive “hot” TME and develop a corresponding stratification model to maximize ICIs-efficacy in Hepatocellular Carcinoma (HCC).

Methods

Hypoxic scores were designed, and the relevance to immunotherapy responses were validated in pan-cancers through single cell analysis. Multi-omics analysis using the hypoxic scores and immune infiltrate abundance was performed to redefine the ICIs-responsive TME subtype in HCC patients from TCGA (n = 363) and HCCDB database (n = 228). The immune hypoxic stress index (IHSI) was constructed to stratify the ICIs-responsive TME subtype, with exploring biological mechanism in vitro and in vivo. MRI-radiomics models were built for clinical applicability.

Results

The hypoxic scores were lower in the dominant cell-subclusters of responders in pan-cancers. The higher immune infiltrate-normoxic (HIN) subtype was redefined as the ICIs-responsive TME. Stratification of the HIN subtype using IHSI effectively identified ICIs-responders in Melanoma (n = 122) and urological cancer (n = 22). TRAF3IP3, the constituent gene of IHSI, was implicated in ICIs-relevant “immune-hypoxic” crosstalk by stimulating MAVS/IFN-I pathway under normoxic condition. MRI-radiomics models assessing TRAF3IP3 with HIF1A expression (AUC > 0.80) screened ICIs-Responders in HCC cohort (n = 75).

Conclusion

The hypoxic-immune stratification redefined ICIs-responsive TME and provided MRI-Radiomics models for initial ICIs-responders screening, with IHSI facilitating further identification.

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Fig. 1: Stratifying HCC patients into immune-hypoxic TME subtypes.
Fig. 2: Immune-hypoxic TME subtypes relevant to prognosis and ICIs responses.
Fig. 3: Immune-hypoxic stress index (IHSI) to predict ICIs efficacy.
Fig. 4: TRAF3IP3 as hub molecule of “immune-hypoxic” crosstalk to regulate ICIs responses.
Fig. 5: Construction of Non-invasive Radiomics models based on TRAF3IP3.

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Data availability

The datasets used and analyzed in this study are available from the corresponding author on reasonable request.

References

  1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.

    Article  CAS  PubMed  Google Scholar 

  2. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  PubMed  Google Scholar 

  3. Kubli SP, Berger T, Araujo DV, Siu LL, Mak TW. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021;20:899–919.

    Article  CAS  PubMed  Google Scholar 

  4. Pan Y, Fu Y, Zeng Y, Liu X, Peng Y, Hu C, et al. The key to immunotherapy: how to choose better therapeutic biomarkers for patients with non-small cell lung cancer. Biomark Res. 2022;10:9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dawkins J, Webster RM. The hepatocellular carcinoma market. Nat Rev Drug Discov. 2019;18:13–4.

    Article  CAS  PubMed  Google Scholar 

  6. Bejarano L, Jordāo MJC, Joyce JA. Therapeutic targeting of the tumor micro- environment. Cancer Discov. 2021;11:933–59.

    Article  CAS  PubMed  Google Scholar 

  7. Goliwas KF, Deshane JS, Elmets CA, Athar M. Moving immune therapy forward targeting TME. Physiol Rev. 2021;101:417–25.

    Article  CAS  PubMed  Google Scholar 

  8. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Y, Lazarus J, Steele NG, Yan W, Lee H-J, Nwosu ZC, et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. 2020;10:422–39.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, et al. IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22:358–69.

    Article  CAS  PubMed  Google Scholar 

  11. Chen X, Song E. The theory of tumor ecosystem. Cancer Commun (Lond). 2022;42:587–608.

    Article  PubMed  Google Scholar 

  12. Mortezaee K, Majidpoor J. The impact of hypoxia on immune state in cancer. Life Sci. 2021;286:120057.

    Article  CAS  PubMed  Google Scholar 

  13. Dercle L, Sun S, Seban R-D, Mekki A, Sun R, Tselikas L, et al. Emerging and evolving concepts in cancer immunotherapy imaging. Radiology 2022;286:210518.

    Google Scholar 

  14. Zwanenburg A, Vallières M, Abdalah MA, Aerts HJWL, Andrearczyk V, Apte A, et al. The ImageBiomarker standardization initiative: standardized quantitative radiomics for high- throughput image-based phenotyping. Radiology 2020;295:328–38.

    Article  PubMed  Google Scholar 

  15. Zhu W, Li J, Zhang R, Cai Y, Wang C, Qi S, et al. TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity. EMBO J. 2019;38:e102075.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Deng M, Tam JW, Wang L, Liang K, Li S, Zhang L, et al. TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination. Nat Commun. 2020;11:2193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Su Y, Luo B, Lu Y, Wang D, Yan J, Zheng J, et al. Anlotinib Induces a T cell-inflamed tumor microenvironment by facilitating vessel normalization and enhances the efficacy of PD-1 checkpoint blockade in neuroblastoma. Clin Cancer Res. 2022;28:793–809.

    Article  CAS  PubMed  Google Scholar 

  18. Yu X, Teng X-L, Wang F, Zheng Y, Qu G, Zhou Y, et al. Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. J Exp Med. 2018;215:2463–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang C-B, Feng H-X, Dai C-L. Development and validation of an immune-related prognosis signature associated with hypoxia and ferroptosis in hepatocellular carcinoma. Cancer Med. 2022;11:2329–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen S, Gao Y, Wang Y, Daemen T. The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer. 2022;151:809–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang J, Huang D, Saw PE, Song E. Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 2022;43:523–45.

    Article  CAS  PubMed  Google Scholar 

  22. Jia Y-Z, Liu J, Wang G-Q, Pan H, Huang T-Z, Liu R, et al. HIG1 domain family member 1 A is a crucial regulator of disorders associated with hypoxia. Mitochondrion 2023;69:171–82.

    Article  CAS  PubMed  Google Scholar 

  23. Largeot A, Pagano G, Gonder S, Moussay E, Paggetti J, et al. The B-side of cancer immunity: the underrated tune. Cells 2019;8:449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abou Khouzam R, Zaarour RF, Brodaczewska K, Azakir B, Venkatesh GH, Thiery J, et al. The effect of hypoxia and hypoxia-associated pathways in the regulation of antitumor response: friends or foes? Front Immunol. 2022;13:828875.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Currie G, Hawk KE, Rohren E. The transformational potential of molecular radiomics. J Med Radiat Sci. 2023;70 Suppl 2:77–88.

    Article  PubMed  Google Scholar 

  26. Yue D, Qian J, Chen Z, Zhang B, Chen P, Zhang L, et al. Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with ROS1-rearranged lung adenocarcinoma. J Immunother Cancer. 2021;9:e001967.

    Article  PubMed  PubMed Central  Google Scholar 

  27. D’Anna F, Van Dyck L, Xiong J, Zhao H, Berrens RV, Qian J, et al. DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. Genome Biol. 2020;21:182.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang Y, Mei Q, Liu Y, Li X, Brock MV, Chen M, et al. The safety, efficacy, and treatment outcomes of a combination of low-dose decitabine treatment in patients with recurrent ovarian cancer. Oncoimmunology. 2017;6:e1323619.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Nie J, Wang C, Liu Y, Yang Q, Mei Q, Dong L, et al. Addition of low-dose decitabine to anti-PD-1 antibody camrelizumab in relapsed/refractory classical hodgkin lymphoma. Clin Trial J Clin Oncol. 2019;37:1479–89.

    Article  CAS  PubMed  Google Scholar 

  30. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng Q-R, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–8.

    Article  CAS  PubMed  Google Scholar 

  31. McGrail DJ, Pilie PG, Rashid NU, Voorwerk L, Slagter M, Kok M, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021;32:661–72.

    Article  CAS  PubMed  Google Scholar 

  32. Bai P, Li Y, Zhou Q, Xia J, Wei P-C, Deng H, et al. Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy. Oncoimmunology. 2021;10:1868130.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nielsen JS, Sedgwick CG, Shahid A, Zong Z, Brumme ZL, Yu S, et al. Toward personalized lymphoma immunotherapy: identification of common driver mutations recognized by patient CD8 + T cells. Clin Cancer Res. 2016;22:2226.

    Article  CAS  PubMed  Google Scholar 

  34. Ghorani E, Rosenthal R, McGranahan N, Reading JL, Lynch M, Peggs KS, et al. Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma. Ann Oncol. 2018;29:271–9.

    Article  CAS  PubMed  Google Scholar 

  35. Dillard P, Koksal H, Maggadottir SM, Winge-Main A, Pollmann S, Menard M, et al. Targeting telomerase with an HLA class II-restricted TCR for cancer immunotherapy. Mol Ther. 2021;29:1199–213.

    Article  CAS  PubMed  Google Scholar 

  36. Li M, Tan J, Miao Y, Lei P, Zhang Q. The dual role of autophagy under hypoxia-involvement of interaction between autophagy and apoptosis. Apoptosis 2015;20:769–77.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by National Natural Science Foundation of China (Grant numbers: No.82072670; No.81871916), the Leading Project of the Science and Technology Commission of Shanghai Municipality (Grant number: 21Y21900100), and the Project of Shanghai Municipal Health Commission (Grant number: 202140269).

Author information

Author notes

  1. These authors contributed equally: Li-Na Song, Biao Wang.

Authors and Affiliations

  1. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Li-Na Song, Jia-Liang Cai, Pei-Ling Zhang, Shi-Ping Chen, Zheng-Jun Zhou & Zhi Dai

  2. Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China

    Li-Na Song, Jia-Liang Cai, Pei-Ling Zhang, Shi-Ping Chen, Zheng-Jun Zhou & Zhi Dai

  3. State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China

    Li-Na Song, Jia-Liang Cai, Pei-Ling Zhang, Shi-Ping Chen, Zheng-Jun Zhou & Zhi Dai

  4. Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China

    Biao Wang

  5. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Shi-Ping Chen

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Contributions

Conception and design: ZD; Development of methodology: LNS, BW; Collection and Assembly of Data: JLC. Software: PLZ. Visualization: SPC, ZJZ. Writing Original: LNS. Writing-Review & Editing: ZD Supervision, ZD; Project Administration, ZD; Funding Acquisition, ZD.

Corresponding author

Correspondence to Zhi Dai.

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Ethical consent was granted from the Committee on Ethics of Zhongshan hospital, Fudan University (Approval number: B2019-144R).

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Song, LN., Wang, B., Cai, JL. et al. Stratifying ICIs-responsive tumor microenvironment in HCC: from parsing out immune-hypoxic crosstalk to clinically applicable MRI-radiomics models. Br J Cancer 130, 1356–1364 (2024). https://doi.org/10.1038/s41416-023-02463-z

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