Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

Lebedev, Timofey; Kousar, Rubina; Patrick, Bbumba; Usama, Muhammad; Lee, Meng-Kuei; Tan, Ming; Li, Xingguo

doi:10.3390/cells12060952

Cited by 6 publications

(6 citation statements)

References 77 publications

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“…In line with our data, ARID1A mutation was found to be associated with increased immune activity in other gastrointestinal (GI) cancers, including the enrichment of CD8 + T cells, NK cells and immune-promoting M1 macrophages [33]. In addition, many studies have reported that ARID1A deficiency correlates with microsatellite instability (MSI), genomic features of GI cancers [15]. A high MSI status is known to confer high immunogenic activity in cancer and improve responsiveness to immunotherapy [16].…”

Section: Discussionsupporting

confidence: 87%

“…Tumor-infiltrating T cells are the determinants of immune tolerance and surveillance in tumors [13]. Studies have shown that ARID1A mutations play a role in the tumor immune phenotype, T cell immunity and the tumor immune microenvironment [14][15][16]. However, the functional implications of ARID1A mutations in the anti-tumor immune response in EAC remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Zhang,

Zheng,

Chien

et al. 2023

Cancers

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ARID1A, a member of the chromatin remodeling SWI/SNF complex, is frequently lost in many cancer types, including esophageal adenocarcinoma (EAC). Here, we study the impact of ARID1A deficiency on the anti-tumor immune response in EAC. We find that EAC tumors with ARID1A mutations are associated with enhanced tumor-infiltrating CD8+ T cell levels. ARID1A-deficient EAC cells exhibit heightened IFN response signaling and promote CD8+ T cell recruitment and cytolytic activity. Moreover, we demonstrate that ARID1A regulates fatty acid metabolism genes in EAC, showing that fatty acid metabolism could also regulate CD8+ T cell recruitment and CD8+ T cell cytolytic activity in EAC cells. These results suggest that ARID1A deficiency shapes both tumor immunity and lipid metabolism in EAC, with significant implications for immune checkpoint blockade therapy in EAC.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Zhang,

Zheng,

Chien

et al. 2023

Cancers

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“…[12] Chidamide is one of the histone deacetylase inhibitors, which selectively inhibits histone deacetylase (HDAC) 1, 2, 3, and 10. [6] Chidamide was approved in December 2014 by the China Food and Drug Administration for the treatment of relapsed or refractory PTCL. [6] However, due to the rare occurrence of SPTCL, there are currently few reports on the treatment of SPTCL with Chidamide.…”

Section: Discussionmentioning

confidence: 99%

“…[ 6 ] Chidamide was approved in December 2014 by the China Food and Drug Administration for the treatment of relapsed or refractory PTCL. [ 6 ] However, due to the rare occurrence of SPTCL, there are currently few reports on the treatment of SPTCL with Chidamide. Only 1 case has reported that Chidamide performs well in the treatment of refractory SPTCL.…”

Section: Discussionmentioning

confidence: 99%

Case report: Successful treatment of Chidamide in a refractory/recurrent SPTCL with ARID1A mutation on the basis of CHOP plus auto-HSCT

Zhang,

et al. 2023

Medicine

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Rationale: Subcutaneous panniculitis like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma that belongs to peripheral T cell lymphomas, of which the overall prognosis is poor. Chidamide, a deacetylase inhibitor, has been approved for the treatment of peripheral T cell lymphomas. However, due to the rare occurrence of SPTCL, it is currently unknown whether Chidamide is effective for all SPTCL patients and whether there are molecular markers that can predict its therapeutic effect on SPTCL. Patient concerns and diagnoses: The patient was a sixteen-year-old male and underwent subcutaneous nodule biopsy which showed SPTCL. Next-generation sequencing revealed AT-rich interaction domain 1A (ARID1A) mutation, and positron emission tomography/computed tomography showed scattered subcutaneous fluorodeoxyglucose metabolic lesions throughout the body. Interventions and outcomes: During the first 3 CHOP (cyclophosphamide, doxorubicin, vindesine, and prednisone) treatment, the patient relapsed again after remission, and the successive addition of methotrexate and cyclosporine did not make the patient relapsing again. Then, after adding Chidamide to the last 3 CHOP treatment, the patient was relieved again. The patient underwent autologous hematopoietic stem cell transplantation (auto-HSCT) after completing a total of 8 cycles of chemotherapy, and continued maintenance therapy with Chidamide after auto-HSCT. Currently, the patient has been in continuous remission for 35 months. Lessons subsections: This case is the first report of a refractory/recurrent SPTCL with ARID1A mutation treated with Chidamide. The treatment of Chidamide on the basis of CHOP plus auto-HSCT therapy achieved good results, suggesting that ARID1A may act as a molecular marker to predict the therapeutic effect of Chidamide on SPTCL patients, which helps to improve the precision of SPTCL treatment and the overall prognosis of SPTCL patients.

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“…As a result, such tumors are susceptible to therapy with immune checkpoint inhibitors (McKean et al, 2020). Lebedev et al (2023) investigated the mechanisms underlying the immunomodulatory role of AT-rich interaction domain 1A (ARID1A). ARID1A is the most frequently mutated epigenetic regulator among all human malignancies.…”

Section: Mechanisms Of Resistance Associated With Tumor Propertiesmentioning

confidence: 99%

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

Moskalenko

2024

Regul. Mech. Biosyst.

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Immune checkpoint inhibitors have opened up new possibilities in clinical oncology. Monoclonal antibodies have shown their high clinical efficiency. They block CTLA-4, PD-1, and PD-L1 receptors and activate the immune response. Many patients have stable and even complete responses. However, some patients have primary or acquired resistance. Therefore, the treatment results in this category of patients are not predictable. Mechanisms of resistance to immune checkpoint inhibitors have not been definitively studied. Many theories try to explain the mechanisms of this phenomenon. Our study aimed to structure and combine the data into groups depending on the etiological factor that reduces the immune response. In addition, based on understanding the mechanisms of resistance and the results of recent clinical studies, we aimed to identify the main ways to overcome it. Therefore, mechanisms that lead to resistance may be associated with tumor properties, tumor microenvironment, or patient characteristics. Tumor properties that reduce the immune response include a) low tumor mutation burden and loss of tumor neoantigens, b) changes in the processing or presentation of neoantigens, and c) changes in signaling pathways of tumor development and epigenetic modifications in genes. The tumor microenvironment is represented by stromal and immune cells, extracellular matrix, cytokines, and blood vessels. Each structure can enhance or reduce the immune response and contribute to the acquired resistance to immune checkpoint inhibitors. The effectiveness of the treatment depends not only on the cells in the tumor microenvironment but also on the metabolic background. In addition, the basic characteristics of the patient ( gender, gut microbiota, HLA-I genotype) can modify the immune response. Based on knowledge about the mechanisms of resistance to immune checkpoint inhibitors, several therapeutic strategies aimed at activating antitumor activity have been evaluated. All of them are based on combining immune checkpoint inhibitors with other drugs. One of the most common options is a combination of PD-1/PD-L1 and CTLA-4 inhibitors. Alternative immune checkpoints are TIM-3, LAG-3, TIGIT and VISTA. Combining immunotherapy with chemotherapy, targeted therapy, neoangiogenesis inhibitors, epigenetic modifiers, PARP or TGF-β inhibitors enhances antitumor response by preventing depletion of effector T cells, enhancing T cell infiltration in the tumor, changes on the tumor microenvironment, and decreasing the accumulation of immunosuppressive cells. This review explores the biological mechanisms of resistance and potential ways of solving this problem.

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Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

Cited by 6 publications

References 77 publications

ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma

ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma

Case report: Successful treatment of Chidamide in a refractory/recurrent SPTCL with ARID1A mutation on the basis of CHOP plus auto-HSCT

Biological mechanisms of resistance to immune checkpoint inhibitors and overcoming this resistance: Challenges in medical oncology

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