Identification of intratumor bacteria-associated prognostic risk score in adrenocortical carcinoma.

A landmark study by Poore et al. showed intratumor bacteria (ITBs) playing a critical role in most cancers by reproduction of The Cancer Genome Atlas (TCGA) transcriptome data. A recent study by Salzberg et al. argued that ITBs, being overstated as a methodology by Poore et al., were problematic. We previously reported that ITBs were prognostic in adrenocortical carcinoma (ACC), a highly aggressive rare disease using data by Poore et al., and here, we aimed to answer whether ITBs truly existed and were prognostic in ACC. ACC samples from our institutes underwent 16S rRNA sequencing [adrenocortical carcinoma blocks from Huashan Hospital and China Medical University (HS) cohort]. The ITB profile was compared to TCGA data processed by Poore et al. (TCGA-P) and TCGA data processed by Salzberg et al. (TCGA-S), respectively. The primary outcome was overall survival (OS). A total of 26 ACC cases (HS cohort) and 10 paraffin controls were sequenced. The TCGA cohort encompassed 77 cases. Two and four amid the top 10 abundant genera in HS cohort were not detected in TCGA-P and TCGA-S, respectively. Neither was alpha or beta diversity associated with survival nor could ACC be subtyped by ITB signature in the HS cohort. Notably, a five-genera ITB risk score (Corynebacterium, Mycoplasma, Achromobacter, Anaerococcus, and Streptococcus) for OS trained in the HS cohort was validated in both TCGA-P and TCGA-S cohorts and was independently prognostic. Whereas ITB signature on the whole may not be associated with ACC subtypes, certain ITB features are associated with prognosis, and a risk score could be generated and validated externally. IMPORTANCE: In this report, we looked at the role of ITBs in ACC in patients with different race and sequencing platforms. We found a five-genera ITB risk score consistently predicted overall survival in all cohorts. We conclude that certain ITB features are universally pathogenic to ACC.

Corrigendum: Development of a phagocytosis- dependent gene signature to predict prognosis and response to checkpoint inhibition in clear-cell renal cell carcinoma.

[This corrects the article DOI: 10.3389/fimmu.2022.853088.].

Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis.

Cuproptosis is a newly discovered cell death induced by excessive copper in mitochondria distinct from any known forms of apoptosis. Role of cuproptosis has not been well-reported in cancer, especially in clear-cell renal cell carcinoma (ccRCC). We comprehensively interrogated cuproptotic gene signature in ccRCC by reproducing multi-omics datasets and found cuproptosis was decreased in ccRCC compared with normal kidney. Cuproptosis identified a subgroup with significantly better prognosis. Functional annotation supported increased tricarboxylic acid cycle activity and decreased hypoxia signaling corroborated by metabolomics. Cuproptotic tumors showed decreased angiogenesis but were sensitive to Sunitinib and Sorafenib. Cuproptotic level in ccRCC cell lines showed robust negative correlation with copper ionophore Elesclomol. All findings support a respiratory subtype of ccRCC identified by cuproptosis.

Development of a Phagocytosis-Dependent Gene Signature to Predict Prognosis and Response to Checkpoint Inhibition in Clear-Cell Renal Cell Carcinoma.

Aim: The action of immune checkpoint inhibition (ICI) largely depends on antibody-dependent cellular phagocytosis (ADCP). We thus aim to develop ADCP-based ccRCC risk stratification as both prognostic and therapeutic markers of ICI. Method: Genomic data from multiple public datasets (TCGA, etc.) were integrated. A cancer-intrinsic ADCP gene set for ccRCC tailored from a recent report was constructed based on the association with prognosis, immune infiltrates, and response to ICI. Therapeutic potential was profiled using genome-drug sensitivity datasets. Results: ADCP genes were selected from a recent CRISPR/Cas9 screen report. Following a four-module panel based on clinical traits, we generated a six-gene signature (ARPC3, PHF19, FKBP11, MS4A14, KDELR3, and CD1C), which showed a strong correlation with advanced grade and stage and worsened prognosis, with a nomogram showing predictive efficacies of 0.911, 0.845, and 0.867 (AUC) at 1, 3, and 5 years, respectively. Signatures were further dichotomized, and groups with a higher risk score showed a positive correlation with tumor mutation burden, higher expressions of inhibitory checkpoint molecules, and increased antitumor immune infiltrates and were enriched for antitumor immune pathways. The high risk-score group showed better response to ICI and could benefit from TKIs of axitinib, tivozanib, or sorafenib, preferentially in combination, whereas sunitinib and pazopanib would better fit the low risk-score group. Conclusion: Here we showed a six-gene ADCP signature that correlated with prognosis and immune modulation in ccRCC. The signature-based risk stratification was associated with response to both ICI and tyrosine kinase inhibition in ccRCC.