Gene Expression Profiles Associated with A Simple and Reliable Myeloid Signature for HCC

ABSTRACT: BACKGROUND & AIMS: Despite the increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the balance of the tumor-associated myeloid response and its translational value. We aimed to construct a simple and reliable signature of local myeloid responses in hepatocellular carcinoma (HCC). METHODS: Using in situ immunohistochemistry (IHC), we assessed myeloid features that revealed the distribution of major myeloid subtypes in both the peri- and intratumoral regions of HCC. A signature was constructed using an L1-penalized Cox regression model based on the postsurgery recurrence data from a training subset (n = 244) that was validated in the testing subset (n = 244) and independent internal (n = 341) and external (n = 348) cohorts. Multiplexed immunofluorescence staining, flow cytometry and transcriptomic analyses were performed to examine the immunological deviations associated with the myeloid signature. Further, we built nomograms to provide a more robust and personalized prognosis for HCC patients. RESULTS: A 2-feature-based, myeloid-specific prognostic signature, namely the myeloid response score (MRS), was constructed. The increase in the MRS was associated with a change in the predominant myeloid populations from CD169+ macrophages (Mφs) in MRSlow HCCs to CD15+CD11b+ neutrophils and CD11b+CD169- Mφs in MRShigh tumors, suggesting a shift in the balance of the myeloid response from antitumor to protumor activities. This alteration was also accompanied by the enhancement of CD8+ T cell exhaustion patterns, including impaired cytotoxic potential and elevated programmed cell death protein 1 (PD-1) expression. The MRS and the MRS-based nomograms had higher accuracy for predicting recurrence and patient survival than the Barcelona Clinic Liver Cancer (BCLC) and tumor-node-metastasis (TNM) staging systems and were validated in a multicenter cohort of HCC patients. Moreover, in a separate cohort of 51 patients, we provided evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC. CONCLUSIONS: We identified and validated a descriptive and prognostic myeloid signature for HCC. HCC tissues with low, intermediate, and high MRS estimates represent tumors with immunocompetent, immunodeficient, and immunosuppressive subtypes, respectively. This technically simple and reliable myeloid signature shows remarkable prognostic potential for HCC after resection and could serve as the basis for the stratification of HCC immune subtypes to aid in a wide range of clinical decisions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134921 | GEO | 2019/07/27

REPOSITORIES: GEO