Stratifying ICIs-responsive Tumor Microenvironment in HCC: from Parsing out Immune-hypoxic Crosstalk to Clinically Applicable MRI-radiomics Models

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Feb 14

PMID 38355839

Authors

Li-Na Song

Biao Wang

Jia-Liang Cai

Pei-Ling Zhang

Shi-Ping Chen

Zheng-Jun Zhou

Zhi Dai

Affiliations

Soon will be listed here.

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.

References

Finn R, Qin S, Ikeda M, Galle P, Ducreux M, Kim T . Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020; 382(20):1894-1905. DOI: 10.1056/NEJMoa1915745. View

Llovet J, Kelley R, Villanueva A, Singal A, Pikarsky E, Roayaie S . Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7(1):6. DOI: 10.1038/s41572-020-00240-3. View

Kubli S, Berger T, Araujo D, Siu L, Mak T . Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov. 2021; 20(12):899-919. DOI: 10.1038/s41573-021-00155-y. View

Pan Y, Fu Y, Zeng Y, Liu X, Peng Y, Hu C . The key to immunotherapy: how to choose better therapeutic biomarkers for patients with non-small cell lung cancer. Biomark Res. 2022; 10(1):9. PMC: 8900392. DOI: 10.1186/s40364-022-00355-7. View

Dawkins J, Webster R . The hepatocellular carcinoma market. Nat Rev Drug Discov. 2018; 18(1):13-14. DOI: 10.1038/nrd.2018.146. View

Bejarano L, Jordao M, Joyce J . Therapeutic Targeting of the Tumor Microenvironment. Cancer Discov. 2021; 11(4):933-959. DOI: 10.1158/2159-8290.CD-20-1808. View

Goliwas K, Deshane J, Elmets C, Athar M . Moving Immune Therapy Forward Targeting TME. Physiol Rev. 2020; 101(2):417-425. PMC: 8428923. DOI: 10.1152/physrev.00008.2020. View

Chen D, Mellman I . Elements of cancer immunity and the cancer-immune set point. Nature. 2017; 541(7637):321-330. DOI: 10.1038/nature21349. View

Zhang Y, Lazarus J, Steele N, Yan W, Lee H, Nwosu Z . Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis. Cancer Discov. 2020; 10(3):422-439. PMC: 7224338. DOI: 10.1158/2159-8290.CD-19-0958. View

10.

Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T . IL-2 regulates tumor-reactive CD8 T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021; 22(3):358-369. DOI: 10.1038/s41590-020-00850-9. View

11.

Chen X, Song E . The theory of tumor ecosystem. Cancer Commun (Lond). 2022; 42(7):587-608. PMC: 9257988. DOI: 10.1002/cac2.12316. View

12.

Mortezaee K, Majidpoor J . The impact of hypoxia on immune state in cancer. Life Sci. 2021; 286:120057. DOI: 10.1016/j.lfs.2021.120057. View

13.

Zwanenburg A, Vallieres M, Abdalah M, Aerts H, Andrearczyk V, Apte A . The Image Biomarker Standardization Initiative: Standardized Quantitative Radiomics for High-Throughput Image-based Phenotyping. Radiology. 2020; 295(2):328-338. PMC: 7193906. DOI: 10.1148/radiol.2020191145. View

14.

Zhu W, Li J, Zhang R, Cai Y, Wang C, Qi S . TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity. EMBO J. 2019; 38(18):e102075. PMC: 6745499. DOI: 10.15252/embj.2019102075. View

15.

Deng M, Tam J, Wang L, Liang K, Li S, Zhang L . TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination. Nat Commun. 2020; 11(1):2193. PMC: 7198545. DOI: 10.1038/s41467-020-16014-0. View

16.

Su Y, Luo B, Lu Y, Wang D, Yan J, Zheng J . 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. 2021; 28(4):793-809. PMC: 9377760. DOI: 10.1158/1078-0432.CCR-21-2241. View

17.

Yu X, Teng X, Wang F, Zheng Y, Qu G, Zhou Y . Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. J Exp Med. 2018; 215(9):2463-2476. PMC: 6122976. DOI: 10.1084/jem.20180397. View

18.

Yang C, Feng H, Dai C . Development and validation of an immune-related prognosis signature associated with hypoxia and ferroptosis in hepatocellular carcinoma. Cancer Med. 2022; 11(11):2329-2341. PMC: 9160815. DOI: 10.1002/cam4.4556. View

19.

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(5):809-824. PMC: 9543189. DOI: 10.1002/ijc.34045. View

20.

Zhang J, Huang D, Saw P, Song E . Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 2022; 43(7):523-545. DOI: 10.1016/j.it.2022.04.010. View