Tumor biology, immune infiltration and liver function define seven hepatocellular carcinoma subtypes linked to distinct drivers, survival and drug response.

BACKGROUND & AIMS: Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). METHODS: We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. RESULTS: Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. CONCLUSIONS: Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities.

HGH1 and the immune landscape: a novel prognostic marker for immune-desert tumor microenvironment identification and immunotherapy outcome prediction in human cancers.

HGH1 homolog, a protein-coding gene, plays a crucial role in human growth and development. However, its role in human cancer remains unclear. For the first time, this study comprehensively evaluated the potential involvement of HGH1 in cancer prognosis and immunological function. To achieve this, data from various databases, including The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, cBioPortal, Tumor Immune Estimation Resource and Immune Cell Abundance Identifier, were collated, as well as from one large clinical study, three immunotherapy cohorts and in vitro experiments. This study aims to elucidate the role of HGH1 expression in cancer prognosis and immune response. Our findings revealed a significant association between increased HGH1 expression and a worse prognosis across various cancer types. Predominantly, copy number variations were identified as the most common genetic mutations. Additionally, HGH1 was observed to not only regulate cell cycle-related functions to promote cell proliferation but also influence autoimmunity-related functions within both the innate and adaptive immune systems, along with other relevant immune-related signaling pathways. Gene set enrichment analysis and gene set variation analysis were used to substantiate these findings. HGH1 overexpression contributed to an immune-deficient (immune-desert) tumor microenvironment, which was characterized by a significant expression of immune-related features such as immune-related gene and pathway expression and the number of immune-infiltrating cells. Furthermore, the correlation between HGH1 expression and tumor mutational burden in four cancers and microsatellite instability in eight cancers was observed. This suggests that HGH1 has potential as an immunotherapeutic target. Immunotherapy data analysis supports this notion, demonstrating that patients with low HGH1 expression treated with immune checkpoint inhibitors exhibit improved survival rates and a higher likelihood of responding to immunotherapy than patients with high HGH1 expression. Collectively, these findings highlight the significant role of HGH1 in human cancers, illuminating its involvement in tumorigenesis and cancer immunity. Elevated HGH1 expression was identified to be indicative of an immune-desert tumor microenvironment. Consequently, the targeting of HGH1, particularly in combination with immune checkpoint inhibitor therapy, holds promise for enhancing therapeutic outcomes in patients with cancer.

Exploring immunotherapy in colorectal cancer.

Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability-high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.

Anti­VEGF antibody triggers the effect of anti­PD­L1 antibody in PD­L1low and immune desert­like mouse tumors.

The efficacy of programmed cell death­ligand 1 (PD­L1)/programmed cell death protein 1 (PD­1) blockade therapy has been demonstrated but is limited in patients with PD­L1low or immune desert tumors. This limitation can be overcome by combination therapies that include anti­vascular endothelial growth factor (VEGF) therapy. Such combinations have been investigated in clinical trials for a number of cancer types; however, evidence on the mechanisms underlying their effects in these types of patients is still not sufficient. Therefore, the present study investigated the efficacy and effects on CD8+ T cell and C­X­C motif chemokine receptor 3 (CXCR3) ligand expression in tumors by combining anti­PD­L1 and anti­VEGF antibodies using an OV2944­HM­1 mouse model with PD­L1low and immune desert­like phenotypes. Although the model exhibited anti­PD­L1 insensitivity, anti­PD­L1 antibody treatment combined with anti­VEGF antibody inhibited tumor growth compared with anti­VEGF monotherapy, which itself inhibited tumor growth compared with the control treatment on Day 25. In combination­treated mice, a higher percentage of CD8+ T cells and higher levels of CXCR3 ligands were observed in tumor tissues compared with those in the anti­VEGF antibody treatment group, which was not significantly different from control treatment on Day 8. The increase in the intratumoral percentage of CD8+ T cells following the combination treatment was reversed by CXCR3 blocking to the same level as the control. In an anti­PD­L1 insensitive model with PD­L1low and immune desert­like phenotypes, although anti­PD­L1 antibody alone was not effective, anti­PD­L1 antibody in combination with anti­VEGF antibody exhibited antitumor combination efficacy with an increase of CD8+ T cell infiltration, which was suggested to be dependent on the increase of intratumoral CXCR3 ligands. This mechanism could explain the efficacy of anti­PD­L1 antibody and anti­VEGF antibody combination therapy in the clinical setting.

Immune deserts in head and neck squamous cell carcinoma: A review of challenges and opportunities for modulating the tumor immune microenvironment.

Immunotherapy revolutionized cancer treatment but has yet to elicit durable responses in the majority of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is generally characterized by a high tumor mutational burden, which has translated to a large neoantigen load that could prime the immune system to recognize and eliminate malignant cells. Studies are increasingly showing, however, that HNSCC is an "immune desert" tumor that can hijack multiple parts of the tumor immunity cycle in order to evade immune recognition and suppress immune system activation. Herein we will review how HNSCC tumors modulate their architecture, cellular composition, and cytokine milieu to maximize immunosuppression; as well as relevant therapeutic opportunities and emerging issues facing the field of HNSCC immuno-oncology.

Cancer-associated fibroblasts: Key players in shaping the tumor immune microenvironment.

Cancer immunotherapies have rapidly changed the therapeutic landscape for cancer. Nevertheless, most of the patients show innate or acquired resistance to these therapies. Studies conducted in recent years have highlighted an emerging role of cancer-associated fibroblasts (CAFs) in immune regulation that shapes the tumor immune microenvironment (TIME) and influences response to cancer immunotherapies. In this review, we outline recent advances in the understanding of phenotypic and functional heterogeneity of CAFs. We will focus on emerging roles of CAFs in shaping the TIME, especially under a framework of tumor immunity continuum, and discuss current and future CAF-targeting therapeutic strategies in particular in the context of optimizing the success of immunotherapies.

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. METHODS: Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario. RESULTS: PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. CONCLUSIONS: In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.