Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies

Xiong, Jia; Wang, Qingqing

doi:10.1016/j.hbpd.2022.07.006

Cited by 7 publications

(7 citation statements)

References 87 publications

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“…[ 5,6 ] Increasing evidence reveals that the clinical response to anti‐PD‐1/PD‐L1 is highly dependent on PD‐L1 expression on tumor cells and T lymphocyte infiltration. [ 7,8 ] Therefore, an in‐depth understanding of the regulatory process of PD‐L1 expression may facilitate the development of novel therapeutic strategies to improve the efficacy of PD‐1/PD‐L1 blockade.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion

Zhang

Man

et al. 2023

Advanced Science

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Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and novel treatment strategies are urgently needed. Mitochondria are key regulators of cellular homeostasis and potential targets for tumor therapy. Here, the role of mitochondrial translocator protein (TSPO) in the regulation of ferroptosis and antitumor immunity is investigated and the potential therapeutic implications for HCC are assessed. TSPO is highly expressed in HCC and associated with poor prognosis. Gain-and loss-of-function experiments present that TSPO promotes HCC cell growth, migration, and invasion in vitro and in vivo. In addition, TSPO inhibits ferroptosis in HCC cells via enhancing the Nrf2-dependent antioxidant defense system. Mechanistically, TSPO directly interacts with P62 and interferes with autophagy, leading to the accumulation of P62. The P62 accumulation competes with KEAP1, preventing it from targeting Nrf2 for proteasomal degradation. Furthermore, TSPO promotes HCC immune escape by upregulating PD-L1 expression through Nrf2-mediated transcription. Notably, TSPO inhibitor PK11195 combines with anti-PD-1 antibody showing a synergistic anti-tumor effect in a mouse model. Overall, the results demonstrated that mitochondrial TSPO promotes HCC progression by inhibiting ferroptosis and antitumor immunity. Targeting TSPO can be a promising new strategy for HCC treatment.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion

Zhang

Man

et al. 2023

Advanced Science

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“…Spy of this phenomenon is the high rate of primary progressors (PP), reported as high as 37% with nivolumab, 33% with pembrolizumab, 45.2% with durvalumab, and 49.4% with tislelizumab. The mechanism of HCC primary resistance to ICIs seems to encompass both tumor intrinsic and micro-environment (TME) levels [14]. Among the former, WNT/CTNNTB1 somatic mutation has the soundest evidence to promote HCC immune escape [15], along with the expression of multiple immune checkpoints such as lymphocyte-activation gene 3 (LAG-3), fibrinogen-like protein1(FGL1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT)-nectin cell adhesion molecule 2 (NECTIN2) and CD 155.…”

Section: Introductionmentioning

confidence: 99%

“…TIGIT interaction with NECTIN2 shapes a cancer-promoting immune suppressive environment [14,27,28] Abbreviations: LAG3, lymphocyte-activation gene 3; FGL1, fibrinogen-like protein1; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; NK, natural killers; CTLA4, Cytotoxic T-Lymphocyte Antigen 4; ICOS, Inducible T-cell costimulator.…”

Section: Introductionmentioning

confidence: 99%

Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle

Salani

Genovesi

Vivaldi

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

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“…He et al (2021) described WTAP in their literature as a protective factor, and the opposite was true for Tang et al (2018) Advances in science and technology in recent years have deepened our horizon of the immune system and its response to tumor cells. The tumor immunotherapy is to employ passive or active immunity against malignant tumors by using the immune system to precisely target tumors (Xiong and Wang, 2022). We also notice the term "TME," which infers to the tumor microenvironment (TME).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis about prognostic and immunological role of WTAP in pan-cancer

et al. 2022

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Background: Wilms tumor 1-associated protein (WTAP) plays a critical role in ribonucleic acid (RNA) methylation of N6 adenosine (m6A) modification, which is closely related with varieties of biological process. However, the role of WTAP in cancers remains to be determined. This study is designed to demonstrate the prognostic landscape of WTAP in pan-cancer and explore the relationship between WTAP expression and immune infiltration.Methods: Here, we investigated the expression level and prognostic role of WTAP in pan-cancer using multiple databases, including PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, applying the GEPIA and TIMER databases, we illustrated the correlations between WTAP expression and immune infiltration in tumors, especially liver hepatocellular carcinoma (LIHC), and esophageal carcinoma (ESCA).Results: WTAP had significant higher expression levels in tumor tissues of ESCA, LIHC, etc., while lower expression levels in those of bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), etc. And WTAP demonstrated multifaceted prognostic value in cancers. Of our interests, WTAP exerted a harmful effect on LIHC patient for overall survival (OS) and progression free survival (PFS). WTAP expression also significantly associated with the infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DC) in LIHC but not ESCA. Furthermore, combined analysis about WTAP expression level and immune cell specific gene markers implied WTAP correlates with regulatory cells (T reg) infiltration in LIHC and ESCA.Conclusion: The m6A regulator WTAP can serve as a prognostic biomarker for certain tumor types in pan-cancer and potentially result from immune cell infiltration.

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Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies

Cited by 7 publications

References 87 publications

Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion

Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion

Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle

Comprehensive analysis about prognostic and immunological role of WTAP in pan-cancer

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