Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma

Yang, Cheng; Gunasegaran, Bavani; Singh, Harsimran; Dutertre, Charles‐Antoine; Loh, Chiew Yee; Lim, Jia Qi; Crawford, Jeremy Chase; Lee, Hong Kai; Zhang, Xiaomeng; Lee, Bernett; Becht, Étienne; Lim, Wan Jun; Yeong, Joe Poh Sheng; Chan, Chung Yip; Chung, Alexander Yaw Fui; Goh, Brian K. P.; Chow, Pierce K. H.; Chan, Jerry Kok Yen; Ginhoux, Florent; Tai, David; Chen, Jinmiao; Lim, Seng Gee; Zhai, Weiwei; Choo, Su Pin; Newell, Evan W.

doi:10.1016/j.immuni.2021.06.013

Cited by 82 publications

(88 citation statements)

References 75 publications

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“…This observation is consistent with that of Li et al, who found that tumor metastasis was facilitated by elevated miR-301a levels, the latter of which correlated with subsequent antitumor-immunity and suppression of CD8+ T cell recruitment (30). Several studies have reported that tumor invasion and immune environment play significant roles in survival outcome and immunotherapy response in cancer patients (31)(32)(33). We propose that determining the expression levels of ACSL4 and status of CD8+ T cell infiltration may be useful for clinicians to better predict the prognosis of patients who undergo BLCA immunotherapy.…”

Section: Discussionsupporting

confidence: 89%

ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer

et al. 2021

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ObjectiveThis study aimed to explore the role of ACSL4 in CD8+ T cell tumor infiltration and outcomes of bladder cancer (BLCA) patients after immunotherapy.MethodsThe correlation between ACSL4 expression and tumor infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource database. The prognostic significance of ACSL4 in BLCA was analyzed using Kaplan–Meier curves. Immunohistochemistry was used to detect CD8+ T cell infiltration in tumors with high and low ACSL4 expression obtained from patients at the Fudan University Shanghai Cancer Center. The relationships between immune checkpoint genes and immune response were analyzed using The Cancer Genome Atlas and IMvigor 210 cohorts. The molecular functions, cellular components, and biological processes involving ACSL4 were explored using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment pathway analyses.ResultsThe expression level of ACSL4 was significantly correlated with the infiltration of CD8+ T cells in BLCA tumors (r = 0.192, P = 2.22e-04). Elevated ACSL4 was associated with suppressed tumor progression and better outcomes for BLCA patients. The higher expression level of ACSL4 predicted better immunotherapeutic responses and was associated with higher expression levels of core immune checkpoint genes, including CD274, CTLA4, PDCD1, and LAG3, compared with the low ACSL4 expression group.ConclusionThis study demonstrated for the first time that elevated ACSL4 correlated significantly with CD8+ T cell infiltration and contributed to better immunotherapeutic responses in BLCA patients. Furthermore, ACSL4 serves as a novel biomarker for predicting patient outcomes after immunotherapeutic treatments, which may improve the development of individualized immunotherapy for BLCA.

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Section: Discussionsupporting

confidence: 89%

ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer

et al. 2021

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“…The aim of this Core and Pol vaccine was to induce mainly a Th1, cellular response capable of clearing HBV infection. This therapeutic vaccine may need to be part of a combination therapy with agents that lower HBsAg [23,36,49,56,57] and/or reverse T-cell exhaustion [58]. This needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

A Therapeutic Hepatitis B Virus DNA Vaccine Induces Specific Immune Responses in Mice and Non-Human Primates

et al. 2021

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Despite the availability of an effective prophylactic vaccine for more than 30 years, nearly 300 million people worldwide are chronically infected with the hepatitis B virus (HBV), leading to 1 death every 30 s mainly from viral hepatitis-related cirrhosis and liver cancer. Chronic HBV patients exhibit weak, transient, or dysfunctional CD8+ T-cell responses to HBV, which contrasts with high CD8+ T-cell responses seen for resolvers of acute HBV infection. Therefore, a therapeutic DNA vaccine was designed, expressing both HBV core and polymerase proteins, and was sequence optimized to ensure high protein expression and secretion. Although the vaccine, administered intramuscularly via electroporation, had no effect on plasma viral parameters in a mouse model of persistent HBV infection, it did induce robust HBV-specific immune responses in healthy and adeno-associated hepatitis B virus (AAV-HBV) infected mice as well as in healthy non-human primates.

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“…Virus-specific CD8 T cells may be coincidently present in the tumor microenvironment of HCC. This argument is supported by a recent study, in which the investigators identified not only tumor-specific CD8 T RM cells but also HBV-specific CD8 T RM cells from HCC-infiltrating T cells using peptide-major histocompatibility complex tetramers and single cell RNA sequencing [27]. It indicates that tumor-infiltrating CD8 T RM cells are not highly tumor-specific in HCC, especially in virus-associated HCC.…”

Section: Discussionmentioning

confidence: 82%

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy

Shen

Yeh

Jeng

et al. 2021

Cancers

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Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 TRM; CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 TRM and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 TRM, and CD39+ or PD-L1+ subsets of CD8 TRM were correlated with tumor response and overall survival (OS). Results: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0–92.6%) of tumor-infiltrating CD8 T cells were TRM. In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 TRM cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 TRM-high, CD39+ CD8 TRM-high, and PD-L1+ CD8 TRM-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 TRM-high, CD39+ CD8 TRM-high, or PD-L1+ CD8 TRM-high, tumors, had significantly prolonged OS (p = 0.0429). Conclusions: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 TRM or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.

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Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma

Cited by 82 publications

References 75 publications

ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer

ACSL4 Expression Is Associated With CD8+ T Cell Infiltration and Immune Response in Bladder Cancer

A Therapeutic Hepatitis B Virus DNA Vaccine Induces Specific Immune Responses in Mice and Non-Human Primates

Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy

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