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Zhang X, Yang L, Gu Y, Wu J, Mei X, Guo S. Predictive Value of Serum β2-Microglobulin for 28-Day Mortality in Sepsis Patients in the Emergency Department. Infect Drug Resist 2025; 18:2365-2376. [PMID: 40357421 PMCID: PMC12067717 DOI: 10.2147/idr.s519987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 05/03/2025] [Indexed: 05/15/2025] Open
Abstract
Background Sepsis is an infection-induced systemic inflammatory response syndrome with high morbidity and mortality. β2-microglobulin (β2-MG), a low-molecular-weight protein involved in immune processes, shows potential for predicting the prognosis of various diseases. However, its role in sepsis prognosis remains unclear, necessitating further exploration. Objective This study aimed to evaluate the predictive value of serum β2-MG for 28-day mortality in sepsis patients and compare it with traditional indicators such as sequential organ failure assessment (SOFA) scores and lactate (Lac) levels. Methods A total of 346 sepsis patients were included in this single-center retrospective study conducted at the emergency department of Beijing Chao-Yang Hospital. Clinical and biochemical indicators, including β2-MG, SOFA scores, and Lac levels, were collected. Predictive ability was assessed using receiver operating characteristic (ROC) curve analysis and binary logistic regression models, and β2-MG was compared to SOFA scores and Lac levels. Results β2-MG was significantly correlated with 28-day mortality and identified as an independent risk factor (P<0.001, OR=1.142, 95% CI: 1.083-1.204). The sensitivity of β2-MG was 94%, and its specificity was 77% for predicting 28-day mortality. Combining β2-MG with SOFA scores increased sensitivity to 94%, while combining it with Lac improved specificity to 88.9%. ROC analysis showed that β2-MG's predictive accuracy improved significantly when combined with these indicators. Conclusion The serum level of β2-MG is an independent predictor of 28-day mortality in sepsis patients. While less sensitive and specific than SOFA scores and lactate, combining β2-MG with these markers improves predictive accuracy, offering complementary prognostic value.
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Affiliation(s)
- Xiangqun Zhang
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, People’s Republic of China
| | - Long Yang
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yu Gu
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Junyuan Wu
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, People’s Republic of China
| | - Xue Mei
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, People’s Republic of China
| | - Shubin Guo
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
- Clinical Center for Medicine in Acute Infection, Capital Medical University, Beijing, People’s Republic of China
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2
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Yong C, Liang Y, Wang M, Jin W, Fan X, Wang Z, Cao K, Wu T, Li Q, Chang C. Alternative splicing: A key regulator in T cell response and cancer immunotherapy. Pharmacol Res 2025; 215:107713. [PMID: 40147681 DOI: 10.1016/j.phrs.2025.107713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/03/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Alternative splicing (AS), a key post-transcriptional regulatory mechanism, is frequently dysregulated in cancer, driving both tumor progression and immune modulation. Aberrant AS influences antigen presentation, T cell activation, immune checkpoint regulation, and cytokine signaling, contributing to immune evasion but also presenting unique therapeutic vulnerabilities. Targeting AS has emerged as a promising strategy in cancer immunotherapy. Splicing-derived neoantigens have been identified as potent inducers of CD8⁺ T cell responses, offering potential for personalized treatment. AS modulators such as PRMT5 inhibitor GSK3326595 enhance immunotherapy efficacy by upregulating MHC class II expression and promoting T cell infiltration, while RBM39 inhibitor indisulam induces tumor-specific neoantigens. Furthermore, combining AS-targeting drugs with immune checkpoint inhibitors (ICIs) has demonstrated synergistic effects, improved response rates and overcoming resistance in preclinical models. Despite these advances, challenges remain in optimizing drug specificity and minimizing toxicity. Future efforts should focus on refining AS-targeting therapies, identifying predictive biomarkers, and integrating these approaches into clinical applications. This review highlights the therapeutic potential of AS modulation in cancer immunotherapy and its implications for advancing precision oncology.
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Affiliation(s)
- Caiyu Yong
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Yexin Liang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Minmin Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Weiwei Jin
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Xuefei Fan
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Zhengwen Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Kui Cao
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Tong Wu
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Qian Li
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China
| | - Cunjie Chang
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, PR China.
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Li A, Gonda BL, Codd EM, von Paternos A, Mitchell DR, Herrmann MD, Kalyan P, Flynn SE, Dzu TQ, Gao C, Zhang E, Mendel JJ, Thierauf JC, Sadow PM, Denize T, Yang D, Fintelmann FJ, Fordham JA, Merkin RD, Bhan AK, Huang YC, Raizer J, Faquin WC, Faden DL, Gao X, Park JC, Wirth LJ, Kaluziak ST, Iafrate AJ. Reversible downregulation of HLA class I in adenoid cystic carcinoma. J Immunother Cancer 2025; 13:e011380. [PMID: 40254393 PMCID: PMC12010351 DOI: 10.1136/jitc-2024-011380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 04/03/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Adenoid cystic carcinoma (ACC) is a rare, but lethal cancer with low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite extensive clinical trials, no effective treatments for patients with recurrent or metastatic ACC are available, and ACC mortality rates remain poor. METHODS We employed automated multiplex immunofluorescence (mIF), single-cell RNA sequencing (scRNA-seq) Gene Expression analysis, RNA in-situ hybridization, and spatial transcriptomics analysis to characterize the immune landscape of ACC tumors, ACC metastasis, and normal tissues from regions where ACCs arise. Based on results from these studies, we treated freshly resected ACCs with interferon-γ or a stimulator of the interferon genes (STING) agonist in vitro. Additionally, we included one patient with ACC in a phase 1 clinical study of a novel STING agonist (dazostinag) plus pembrolizumab. RESULTS The mIF analysis revealed that ACC tumors are immunologically "cold", with few tumor-infiltrating T-lymphocytes and low programmed death-ligand 1 (PD-L1) expression. The most striking finding was a very low beta-2-microglobulin (B2M) expression in nearly all ACCs, with only focal expression found in some ACC metastases. mIF and RNA sequencing analyses of normal salivary gland and breast tissues revealed a p63+, NFIB+, basal duct cell population, with similarly low B2M/human leukocyte antigen (HLA) class I expression. Spatial transcriptomics analysis of the focally B2M-positive ACC metastases uncovered the genetic pathway driving upregulation of B2M, an interferon-γ program mediating the reintroduction of HLA-I/B2M; the significantly upregulated genes included IRF1, GBP1, and TAP1. On short-term treatment of primary ACC tissues in vitro with interferon-γ or a STING agonist, we observed strongly upregulated HLA class I/B2M expression. Moreover, treatment of a patient with recurrent, metastatic breast ACC with a STING agonist and pembrolizumab led to a partial response with a 70% tumor reduction. CONCLUSIONS Low B2M/HLA class I expression may explain why ACCs are immunologically cold and the lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in a B2M/HLA-class I low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, as supported by the promising response observed in a patient with metastatic ACC. These findings indicate a potential path to urgently needed immunotherapies.
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Affiliation(s)
- Annie Li
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bianca L Gonda
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Elizabeth M Codd
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Adam von Paternos
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dawn R Mitchell
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Markus D Herrmann
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Prinjali Kalyan
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Samantha E Flynn
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Thuc Q Dzu
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Chengzhuo Gao
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Edwin Zhang
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Julia J Mendel
- Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Julia C Thierauf
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Peter M Sadow
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas Denize
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Diane Yang
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Florian J Fintelmann
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Masachusetts, USA
| | - Jo Anne Fordham
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ross D Merkin
- Department of Medicine, Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Atul K Bhan
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yu-Chung Huang
- Oncology Development, Takeda Pharmaceuticals, Development Center Americas Inc, Lexington, Massachusetts, USA
| | - Jeffrey Raizer
- Oncology Development, Takeda Pharmaceuticals, Development Center Americas Inc, Lexington, Massachusetts, USA
| | - William C Faquin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel L Faden
- Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Xin Gao
- Department of Medicine, Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jong Chul Park
- Department of Medicine, Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lori J Wirth
- Department of Medicine, Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Stefan T Kaluziak
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - A John Iafrate
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Han X, Zhang J, Li W, Huang X, Wang X, Wang B, Gao L, Chen H. The role of B2M in cancer immunotherapy resistance: function, resistance mechanism, and reversal strategies. Front Immunol 2025; 16:1512509. [PMID: 40191187 PMCID: PMC11968357 DOI: 10.3389/fimmu.2025.1512509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Immunotherapy has emerged as a preeminent force in the domain of cancer therapeutics and achieved remarkable breakthroughs. Nevertheless, the high resistance has become the most substantial impediment restricting its clinical efficacy. Beta-2 microglobulin (B2M), the light chain of major histocompatibility complex (MHC) class I, plays an indispensable part by presenting tumor antigens to cytotoxic T lymphocytes (CTLs) for exerting anti-tumor effects. Accumulating evidence indicates that B2M mutation/defect is one of the key mechanisms underlying tumor immunotherapy resistance. Therefore, elucidating the role played by B2M and devising effective strategies to battle against resistance are pressing issues. This review will systematically expound upon them, aiming to provide insight into the potential of B2M as a promising target in anticancer immune response.
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Affiliation(s)
- Xiaowen Han
- Lanzhou University Second Hospital, Lanzhou, China
| | - Jiayi Zhang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Weidong Li
- Lanzhou University Second Hospital, Lanzhou, China
| | | | - Xueyan Wang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Bofang Wang
- Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, China
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Evaristo G, Harmath C, Segal JP, Shergill A, Setia N. Diagnostic Challenges due to a Germline Missense MSH2 Variant in a Patient With Immunotherapy-Responsive Locally Advanced Rectal Adenocarcinoma. Cancer Rep (Hoboken) 2024; 7:e70037. [PMID: 39696980 DOI: 10.1002/cnr2.70037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 08/28/2024] [Accepted: 10/14/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Rapid and accurate identification of mismatch repair (MMR) deficiency and Lynch syndrome is critical in the prognostication and clinical management of patients with colorectal carcinoma. CASE DESCRIPTION We describe here a young woman who developed a locally aggressive rectal adenocarcinoma with intact MMR protein expression by immunohistochemistry and absence of histologic evidence of MMR deficiency-associated increased tumoral immune response. Germline DNA-targeted sequencing identified MSH2 variant p.R711P, initially classified as a variant of undetermined significance. Somatic tumoral DNA analysis revealed the identical MSH2 variant, high tumor mutational burden, and microsatellite instability, in addition to superimposed alterations in β2-microglobulin gene, possibly explaining the altered intratumoral immunity. Consequently, the patient was started on immunotherapy, leading to successful disease control (33 month follow-up). CONCLUSION The findings emphasize the utility of an integrative approach in the assessment of MMR status for determining candidacy for immunotherapy, especially in the setting of missense variants in MMR genes.
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Affiliation(s)
- Gertruda Evaristo
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Carla Harmath
- Department of Radiology, The University of Chicago, Chicago, Illinois, USA
| | - Jeremy P Segal
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
| | - Ardaman Shergill
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA
| | - Namrata Setia
- Department of Pathology, The University of Chicago, Chicago, Illinois, USA
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Zhao H, Luo K, Liu M, Cai Y, Liu S, Li S, Zhao Y, Zhang H. Immune regulation and prognostic prediction model establishment and validation of PSMB6 in lung adenocarcinoma. Front Genet 2024; 15:1458047. [PMID: 39507618 PMCID: PMC11538069 DOI: 10.3389/fgene.2024.1458047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/09/2024] [Indexed: 11/08/2024] Open
Abstract
Lung cancer is one of the most common malignant tumors, and patients are often diagnosed at an advanced stage, posing a substantial risk to human health, so it is crucial to establish a model to forecast the prognosis of patients with lung cancer. Recent research has indicated that proteasome 20S subunit 6 (PSMB6) may be closely associated with anti-apoptotic pathways, and proliferation transduction signals in tumor cells of different tumors. However, the precise role of PSMB6 in the immunoregulatory processes within lung adenocarcinoma (LUAD) is yet to be elucidated. By analyzing the TCGA database, we discovered a positive correlation between the expression of PSMB6 and tumor growth trends, and lung adenocarcinoma patients with elevated PSMB6 expression levels had a worse prognosis. Our findings suggest a close correlation between PSMB6 expression levels, immune cell infiltration and immune checkpoint gene expression, which suggests that PSMB6 may become a new independent prognostic indicator. In addition, we developed a prognostic model of PSMB6-regulated immune infiltration-associated genes by analyzing the link between PSMB6 and the immune microenvironment. This model can not only predict the prognosis of lung adenocarcinoma but also forecasts the patient's reaction to immunotherapy. The validity of this research outcome has been confirmed by the GSE31210 and IMvigor210 cohorts. Analysis of the Kaplan-Meier Plotter database indicates that individuals with elevated levels of PSMB6 expression exhibit a poorer prognosis. Additionally, in vitro experiments demonstrated that knockdown of PSMB6 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells while promoting their apoptosis. Overall, our findings suggest that PSMB6 could remarkably influence the management and treatment of lung adenocarcinoma, opening new avenues for targeted immunotherapeutic strategies.
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Affiliation(s)
- Haiyang Zhao
- Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Nanchong, China
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Innovation Centre for Science and Technology, Nanchong, China
| | - Kexin Luo
- Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Nanchong, China
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Innovation Centre for Science and Technology, Nanchong, China
| | - Meihan Liu
- Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Nanchong, China
- North Sichuan Medical College, Innovation Centre for Science and Technology, Nanchong, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yuanze Cai
- North Sichuan Medical College, Nanchong, China
| | - Siman Liu
- North Sichuan Medical College, Nanchong, China
| | - Shijuan Li
- Nanchong Central Hospital, Nanchong, Sichuan, China
| | - Yongsheng Zhao
- Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Nanchong, China
- Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hongpan Zhang
- Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- North Sichuan Medical College, Nanchong, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Therapeutic Proteins Key Laboratory of Sichuan Province, Nanchong, China
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Zhang Z, Liu Z, Chen L, Wang Z, Zhai Y, Qian P, Zhao Y, Zhu L, Jiang H, Wu X, Shi Q. Liquid Biopsy-Based Accurate Diagnosis and Genomic Profiling of Hard-to-Biopsy Tumors via Parallel Single-Cell Genomic Sequencing of Exfoliated Tumor Cells. Anal Chem 2024; 96:14669-14678. [PMID: 39197101 DOI: 10.1021/acs.analchem.4c03462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2024]
Abstract
Liquid biopsy provides a convenient and safer procedure for the diagnosis and genomic profiling of tumors that are inaccessible to biopsy by analyzing exfoliated tumor cells (ETCs) or tumor-derived cell-free DNA (cfDNA). However, its primary challenge lies in its limited accuracy in comparison to tissue-based approaches. We report a parallel single-ETC genomic sequencing (Past-Seq) method for the accurate diagnosis and genomic profiling of hard-to-biopsy tumors such as cholangiocarcinoma (CCA) and upper tract urothelial carcinoma (UTUC). For CCA, a prospective cohort of patients with suspicious biliary strictures (n = 36) was studied. Parallel single-cell whole genome sequencing and whole exome sequencing were performed on bile ETCs for CCA diagnosis and resolving mutational profiles, respectively, along with bile cfDNA sequenced for comparison. Concordant single-cell copy number alteration (CNA) profiles in multiple ETCs provided compelling evidence for generating a malignant diagnosis. Past-Seq yielded bile-based accurate CCA diagnosis (96% sensitivity, 100% specificity, and positive predictive value), surpassing pathological evaluation (56% sensitivity) and bile cfDNA CNA analysis (13% sensitivity), and generated the best performance in the retrieval tissue mutations. To further explore the applicability of Past-Seq, 10 suspicious UTUC patients were investigated with urine specimens, and Past-Seq exhibited 90% sensitivity in diagnosing UTUC, demonstrating its broad applicability across various liquid biopsies and cancer types.
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Affiliation(s)
- Ziyuan Zhang
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhigang Liu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Lin Chen
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhuo Wang
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Yangyang Zhai
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai Research Center of Biliary Tract Disease, Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Peiyu Qian
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yichun Zhao
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Ling Zhu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
- Fudan Institute of Urology, Fudan University, Shanghai, 200040, China
| | - Xubo Wu
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Qihui Shi
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Department of Hepatopancreatobiliary Surgery, Minhang Hospital and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
- Shanghai Engineering Research Center of Biomedical Analysis Reagents, Fudan Zhang Jiang Institute, Shanghai, 201203, China
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Chong X, Madeti Y, Cai J, Li W, Cong L, Lu J, Mo L, Liu H, He S, Yu C, Zhou Z, Wang B, Cao Y, Wang Z, Shen L, Wang Y, Zhang X. Recent developments in immunotherapy for gastrointestinal tract cancers. J Hematol Oncol 2024; 17:65. [PMID: 39123202 PMCID: PMC11316403 DOI: 10.1186/s13045-024-01578-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/18/2024] [Indexed: 08/12/2024] Open
Abstract
The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.
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Affiliation(s)
- Xiaoyi Chong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Yelizhati Madeti
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Jieyuan Cai
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Wenfei Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Lin Cong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Jialin Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Liyang Mo
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Huizhen Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Siyi He
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Chao Yu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Zhiruo Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Boya Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Yanshuo Cao
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yakun Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China.
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Hai-Dian District, Beijing, 100142, China.
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China.
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9
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Yang K, Halima A, Chan TA. Antigen presentation in cancer - mechanisms and clinical implications for immunotherapy. Nat Rev Clin Oncol 2023; 20:604-623. [PMID: 37328642 DOI: 10.1038/s41571-023-00789-4] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2023] [Indexed: 06/18/2023]
Abstract
Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies. In this Review, we describe the molecular mechanisms of antigen processing and presentation in tumours and their clinical consequences. We examine how various aspects of the antigen-presentation machinery (APM) shape tumour immunity. In particular, we discuss genomic variants in HLA alleles and other APM components, highlighting their influence on the immunopeptidomes of both malignant cells and immune cells. Understanding the APM, how it is regulated and how it changes in tumour cells is crucial for determining which patients will respond to immunotherapy and why some patients develop resistance. We focus on recently discovered molecular and genomic alterations that drive the clinical outcomes of patients receiving immune-checkpoint inhibitors. An improved understanding of how these variables mediate tumour-immune interactions is expected to guide the more precise administration of immunotherapies and reveal potentially promising directions for the development of new immunotherapeutic approaches.
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Affiliation(s)
- Kailin Yang
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Ahmed Halima
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Timothy A Chan
- Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
- National Center for Regenerative Medicine, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
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10
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Astore S, Baciarello G, Cerbone L, Calabrò F. Primary and acquired resistance to first-line therapy for clear cell renal cell carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:517-546. [PMID: 37842234 PMCID: PMC10571064 DOI: 10.20517/cdr.2023.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/26/2023] [Accepted: 07/11/2023] [Indexed: 10/17/2023]
Abstract
The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients' treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.
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Affiliation(s)
- Serena Astore
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | | | - Linda Cerbone
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
| | - Fabio Calabrò
- Medical Oncology, San Camillo Forlanini Hospital, Rome 00152, Italy
- Medical Oncology, IRCSS, National Cancer Institute Regina Elena, Rome 00128, Italy
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11
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Wang Y, Jasinski-Bergner S, Wickenhauser C, Seliger B. Cancer Immunology: Immune Escape of Tumors-Expression and Regulation of HLA Class I Molecules and Its Role in Immunotherapies. Adv Anat Pathol 2023; 30:148-159. [PMID: 36517481 DOI: 10.1097/pap.0000000000000389] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The addition of "avoiding immune destruction" to the hallmarks of cancer demonstrated the importance of cancer immunology and in particular the role of immune surveillance and escape from malignancies. However, the underlying mechanisms contributing to immune impairment and immune responses are diverse. Loss or reduced expression of the HLA class I molecules are major characteristics of human cancers resulting in an impaired recognition of tumor cells by CD8 + cytotoxic T lymphocytes. This is of clinical relevance and associated with worse patients outcome and limited efficacy of T-cell-based immunotherapies. Here, we summarize the role of HLA class I antigens in cancers by focusing on the underlying molecular mechanisms responsible for HLA class I defects, which are caused by either structural alterations or deregulation at the transcriptional, posttranscriptional, and posttranslational levels. In addition, the influence of HLA class I abnormalities to adaptive and acquired immunotherapy resistances will be described. The in-depth knowledge of the different strategies of malignancies leading to HLA class I defects can be applied to design more effective cancer immunotherapies.
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Affiliation(s)
| | - Simon Jasinski-Bergner
- Institute of Medical Immunology
- Institute for Translational Immunology, Medical School "Theodor Fontane", Brandenburg, Germany
| | - Claudia Wickenhauser
- Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale)
| | - Barbara Seliger
- Institute of Medical Immunology
- Department of Good Manufacturing Practice (GMP) Development & Advanced Therapy Medicinal Products (ATMP) Design, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, GermanyLeipzig, Germany
- Institute for Translational Immunology, Medical School "Theodor Fontane", Brandenburg, Germany
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12
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Liu F, Zhong F, Wu H, Che K, Shi J, Wu N, Fu Y, Wang Y, Hu J, Qian X, Fan X, Wang W, Wei J. Prevalence and Associations of Beta2-Microglobulin Mutations in MSI-H/dMMR Cancers. Oncologist 2023; 28:e136-e144. [PMID: 36724040 PMCID: PMC10020813 DOI: 10.1093/oncolo/oyac268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Accepted: 11/29/2022] [Indexed: 02/02/2023] Open
Abstract
Microsatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. β-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P = .026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients.
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Affiliation(s)
- Fangcen Liu
- Department of Pathology, Affiliated Drum Tower Hospital to Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Fangfang Zhong
- Department of Pathology, Margaret Williamson Red House Hospital, Shanghai, People’s Republic of China
| | - Huan Wu
- Department of R&D, OrigiMed, Shanghai, People’s Republic of China
| | - Keying Che
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China
| | - Jiaochun Shi
- Department of R&D, OrigiMed, Shanghai, People’s Republic of China
| | - Nandie Wu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China
| | - Yao Fu
- Department of Pathology, Affiliated Drum Tower Hospital to Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Yue Wang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China
| | - Jing Hu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China
| | - Xiaoping Qian
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China
| | - Xiangshan Fan
- Department of Pathology, Affiliated Drum Tower Hospital to Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Weifeng Wang
- Department of R&D, OrigiMed, Shanghai, People’s Republic of China
| | - Jia Wei
- Corresponding author: Jia Wei, MD, The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China. Tel: +86 13951785234; Fax: +86 25 83317016; E-mail:
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13
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Danishevich AM, Pospehova NI, Stroganova AM, Golovina DA, Nikulin MP, Kalinin AE, Nikolaev SE, Stilidi IS, Lyubchenko LN. Landscape of KRAS, BRAF, and PIK3CA Mutations and Clinical Features of EBV-Associated and Microsatellite Unstable Gastric Cancer. Mol Biol 2023. [DOI: 10.1134/s0026893323010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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14
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A Novel Tongue Squamous Cell Carcinoma Cell Line Escapes from Immune Recognition due to Genetic Alterations in HLA Class I Complex. Cells 2022; 12:cells12010035. [PMID: 36611830 PMCID: PMC9818362 DOI: 10.3390/cells12010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) have made progress in the field of anticancer treatment, but a certain number of PD-L1 negative OSCC patients still have limited benefits from ICI immuno-therapy because of primary immune evasion due to immunodeficiency. However, in existing human OSCC cell lines, cell models that can be used to study immunodeficiency have not been reported. The objective of this study was to establish a PD-L1 negative OSCC cell line, profile whether the presence of mutated genes is associated with immune deficiency, and explore its influence on the immune recognition of CD8+ T cells in vitro. Here, we established a novel tongue SCC cell line (WU-TSC-1), which escapes from immune recognition by antigen presentation defects. This cell line was from a female patient who lacked typical causative factors. The expression of PD-L1 was negative in the WU-TSC-1 primary tumor, transplanted tumor, cultured cells and lipopolysaccharide stimulation. Whole exome sequencing (WES) revealed that WU-TSC-1 harbored missense mutations, loss of copy number and structural variations in human leukocyte antigen (HLA) class I/II genes. The tumor mutation burden (TMB) score was high at 292.28. In addition, loss of heterozygosity at beta-2-microglobulin (B2M)-a component of all HLA class I complex allotypes-was detected. Compared with the commonly used OSCC cell lines, genetic alterations in HLA class I and B2M impeded the proteins' translation and inhibited the activation and killing effect of CD8+ T cells. In all, the WU-TSC-1 cell line is characterized by genetic variations and functional defects of the HLA class I complex, leading to escape from recognition by CD8+ T cells.
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15
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Xu Y, Chen Y, Jiang W, Yin X, Chen D, Chi Y, Wang Y, Zhang J, Zhang Q, Han Y. Identification of fatty acid metabolism-related molecular subtype biomarkers and their correlation with immune checkpoints in cutaneous melanoma. Front Immunol 2022; 13:967277. [PMID: 36466837 PMCID: PMC9716430 DOI: 10.3389/fimmu.2022.967277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 11/04/2022] [Indexed: 10/06/2023] Open
Abstract
PURPOSE Fatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aimed to construct FAM molecular subtypes and identify key prognostic biomarkers in CM. METHODS We used a CM dataset in The Cancer Genome Atlas (TCGA) to construct FAM molecular subtypes. We performed Kaplan-Meier (K-M) analysis, gene set enrichment analysis (GSEA), and TME analysis to assess differences in the prognosis and immune phenotype between subtypes. We used weighted gene co-expression network analysis (WGCNA) to identify key biomarkers that regulate tumor metabolism and immunity between the subtypes. We compared overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) between CM patients with high or low biomarker expression. We applied univariable and multivariable Cox analyses to verify the independent prognostic value of the FAM biomarkers. We used GSEA and TME analysis to investigate the immune-related regulation mechanism of the FAM subtype biomarker. We evaluated the immune checkpoint inhibition (ICI) response and chemotherapy sensitivity between CM patients with high or low biomarker expression. We performed real-time fluorescent quantitative PCR (qRT-PCR) and semi-quantitative analysis of the immunohistochemical (IHC) data from the Human Protein Atlas to evaluate the mRNA and protein expression levels of the FAM biomarkers in CM. RESULTS We identified 2 FAM molecular subtypes (cluster 1 and cluster 2). K-M analysis showed that cluster 2 had better OS and PFS than cluster 1 did. GSEA showed that, compared with cluster 1, cluster 2 had significantly upregulated immune response pathways. The TME analysis indicated that immune cell subpopulations and immune functions were highly enriched in cluster 2 as compared with cluster 1. WGCNA identified 6 hub genes (ACSL5, ALOX5AP, CD1D, CD74, IL4I1, and TBXAS1) as FAM biomarkers. CM patients with high expression levels of the six biomarkers had better OS, PFS, and DSS than those with low expression levels of the biomarkers. The Cox regression analyses verified that the 6 FAM biomarkers can be independent prognostic factors for CM patients. The single-gene GSEA showed that the high expression levels of the 6 genes were mainly enriched in T-cell antigen presentation, the PD-1 signaling pathway, and tumor escape. The TME analysis confirmed that the FAM subtype biomarkers were not only related to immune infiltration but also highly correlated with immune checkpoints such as PD-1, PD-L1, and CTLA-4. TIDE scores confirmed that patients with high expression levels of the 6 biomarkers had worse immunotherapy responses. The 6 genes conveyed significant sensitivity to some chemotherapy drugs. qRT-PCR and IHC analyses verified the expression levels of the 6 biomarkers in CM cells. CONCLUSION Our FAM subtypes verify that different FAM reprogramming affects the function and phenotype of infiltrating immune cells in the CM TME. The FAM molecular subtype biomarkers can be independent predictors of prognosis and immunotherapy response in CM patients.
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Affiliation(s)
- Yujian Xu
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Youbai Chen
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Weiqian Jiang
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiangye Yin
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Dongsheng Chen
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yuan Chi
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yuting Wang
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Julei Zhang
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Qixu Zhang
- Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yan Han
- Department of Plastic and Reconstructive Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
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16
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Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
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Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
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17
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Wang C, Wang Z, Yao T, Zhou J, Wang Z. The immune-related role of beta-2-microglobulin in melanoma. Front Oncol 2022; 12:944722. [PMID: 36046045 PMCID: PMC9421255 DOI: 10.3389/fonc.2022.944722] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/25/2022] [Indexed: 11/23/2022] Open
Abstract
Despite the remarkable success of immunotherapy in the treatment of melanoma, resistance to these agents still affects patient prognosis and response to therapies. Beta-2-microglobulin (β2M), an important subunit of major histocompatibility complex (MHC) class I, has important biological functions and roles in tumor immunity. In recent years, increasing studies have shown that B2M gene deficiency can inhibit MHC class I antigen presentation and lead to cancer immune evasion by affecting β2M expression. Based on this, B2M gene defect and T cell-based immunotherapy can interact to affect the efficacy of melanoma treatment. Taking into account the many recent advances in B2M-related melanoma immunity, here we discuss the immune function of the B2M gene in tumors, its common genetic alteration in melanoma, and its impact on and related improvements in melanoma immunotherapy. Our comprehensive review of β2M biology and its role in tumor immunotherapy contributes to understanding the potential of B2M gene as a promising melanoma therapeutic target.
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Affiliation(s)
- Chuqiao Wang
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ophthalmic Tumor, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zeqi Wang
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ophthalmic Tumor, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tengteng Yao
- Department of Ophthalmology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Jibo Zhou
- Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Orbital Diseases and Ophthalmic Tumor, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jibo Zhou, ; Zhaoyang Wang,
| | - Zhaoyang Wang
- Department of Ophthalmology, Shanghai Tenth People’s Hospital Affiliated to Tongji University, Shanghai, China
- *Correspondence: Jibo Zhou, ; Zhaoyang Wang,
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18
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Tumor Antigenicity and a Pre-Existing Adaptive Immune Response in Advanced BRAF Mutant Colorectal Cancers. Cancers (Basel) 2022; 14:cancers14163951. [PMID: 36010943 PMCID: PMC9405961 DOI: 10.3390/cancers14163951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 11/20/2022] Open
Abstract
Simple Summary BRAF mutant metastatic CRCs (BRAF-mCRCs) are considered a unique clinical entity characterized by a dismal prognosis and that do not respond efficiently to both standard chemotherapy and to orally selective inhibitors of BRAFV600E. In this study, the gene expression profiles of 89 immunotherapy-naïve BRAF-CRCs were generated using the PanCancer IO 360 gene expression panel to improve the knowledge of the mechanisms involved in tumor-suppressive immune functions in BRAF-mCRCs. A significant fraction of BRAF-mCRCs shows a hot/inflamed profile and may be potential candidates for responding to immunotherapy. Only a partial overlap between these hot signatures and the presence of microsatellite instability (MSI) was observed, demonstrating that MSI tumors showed a not differential expression of MHC Class I antigen presentation pathway compared with microsatellite-stable tumors. The analysis of gene expression profiles is a promising strategy both for immune profiling of primary tumors before any treatment and for following the evolution of metastatic disease during therapy. Abstract The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8− tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade.
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Chen MY, Zeng YC, Zhao XH. Chemotherapy- and Immune-Related Gene Panel in Prognosis Prediction and Immune Microenvironment of SCLC. Front Cell Dev Biol 2022; 10:893490. [PMID: 35784467 PMCID: PMC9240612 DOI: 10.3389/fcell.2022.893490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
Small-cell lung cancer (SCLC) is a highly proliferative, invasive lung cancer with poor prognosis. Chemotherapy is still the standard first-line treatment for SCLC, but many patients relapse due to chemoresistance. Along with advances in immunology, it is essential to investigate potential indicators of the immune response and the prognosis of SCLC. Using bioinformatics analysis, we identified 313 differentially expressed genes (DEGs) in SCLC and normal lung samples, and we found that four upregulated genes (TOP2A, CDKN2A, BIRC5, and MSH2) were associated with platinum resistance, while immune-related genes (HLA family genes) were downregulated in SCLC. Then, a prognostic prediction model was constructed for SCLC based on those genes. Immune cell infiltration analysis showed that antigen presentation was weak in SCLC, and TOP2A expression was negatively correlated with CD8+ T cells, while HLA-ABC expression was positively correlated with M1 macrophages, memory B cells, and CD8+ T cells. We also found that TOP2A was related to poor prognosis and inversely correlated with HLA-ABC, which was verified with immunohistochemical staining in 151 SCLC specimens. Our study findings indicated that TOP2A may be a potential prognosis indicator and a target to reverse the immunosuppressive tumor microenvironment of SCLC.
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Affiliation(s)
- Meng-Yu Chen
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Breast Oncology, The Third Hospital of Nanchang, Nanchang, China
| | - Yue-Can Zeng
- Department of Radiation Oncology, Cancer Center, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Xi-He Zhao
- Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Xi-He Zhao,
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20
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Xu G, Luo Y, Wang H, Wang Y, Liu B, Wei J. Therapeutic bispecific antibodies against intracellular tumor antigens. Cancer Lett 2022; 538:215699. [PMID: 35487312 DOI: 10.1016/j.canlet.2022.215699] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 12/16/2022]
Abstract
Bispecific antibodies (BsAbs)-based therapeutics have been identified to be one of the most promising immunotherapy strategies. However, their target repertoire is mainly restricted to cell surface antigens rather than intracellular antigens, resulting in a relatively limited scope of applications. Intracellular tumor antigens are identified to account for a large proportion of tumor antigen profiles. Recently, bsAbs that target intracellular oncoproteins have raised much attention, broadening the targeting scope of tumor antigens and improving the efficacy of traditional antibody-based therapeutics. Consequently, this review will focus on this emerging field and discuss related research advances. We introduce the classification, characteristics, and clinical applications of bsAbs, the theoretical basis for targeting intracellular antigens, delivery systems of bsAbs, and the latest preclinical and clinical advances of bsAbs targeting several intracellular oncotargets, including those of cancer-testis antigens, differentiation antigens, neoantigens, and other antigens. Moreover, we summarize the limitations of current bsAbs, and propose several potential strategies against immune escape and T cell exhaustion as well as some future perspectives.
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Affiliation(s)
- Guanghui Xu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Yuting Luo
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Hanbing Wang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Yue Wang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Baorui Liu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
| | - Jia Wei
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China; Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210008, China.
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Paschen A, Melero I, Ribas A. Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade. ANNUAL REVIEW OF CANCER BIOLOGY 2022. [DOI: 10.1146/annurev-cancerbio-070220-111016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Resistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.
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Affiliation(s)
- Annette Paschen
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site Essen/Düsseldorf, Essen, Germany
| | - Ignacio Melero
- University Clinic of Navarre (CUN) and Centre of Applied Medical Research (CIMA), University of Navarre, Pamplona, Spain
- CIBERONC (Consorcio Centro de Investigación Biomédica en Red de Cáncer), Madrid, Spain
| | - Antoni Ribas
- Department of Medicine, Department of Surgery, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
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22
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Arnold PY. Review: HLA loss and detection in the setting of relapse from HLA-mismatched hematopoietic cell transplant. Hum Immunol 2022; 83:712-720. [DOI: 10.1016/j.humimm.2022.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/09/2022] [Accepted: 03/02/2022] [Indexed: 01/25/2023]
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Garrido MA, Perea F, Vilchez JR, Rodríguez T, Anderson P, Garrido F, Ruiz-Cabello F, Aptsiauri N. Copy Neutral LOH Affecting the Entire Chromosome 6 Is a Frequent Mechanism of HLA Class I Alterations in Cancer. Cancers (Basel) 2021; 13:cancers13205046. [PMID: 34680201 PMCID: PMC8534100 DOI: 10.3390/cancers13205046] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 07/28/2021] [Accepted: 10/07/2021] [Indexed: 01/05/2023] Open
Abstract
Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides by cytotoxic T lymphocytes favoring cancer immune escape during natural tumor evolution. These alterations can be caused by genomic defects, such as loss of heterozygosity at chromosomes 6 and 15 (LOH-6 and LOH-15), where HLA class I genes are located. There is growing evidence indicating that LOH in HLA contributes to the immune selection of HLA loss variants and influences the resistance to immunotherapy. Nevertheless, the incidence and the mechanism of this chromosomal aberration involving HLA genes has not been systematically assessed in different types of tumors and often remains underestimated. Here, we used SNP arrays to investigate the incidence and patterns of LOH-6 and LOH-15 in a number of human cancer cell lines and tissues of different histological types. We observed that LOH in HLA is a common event in cancer samples with a prevalence of a copy neutral type of LOH (CN-LOH) that affects entire chromosome 6 or 15 and involves chromosomal duplications. LOH-6 was observed more often and was associated with homozygous HLA genotype and partial HLA loss of expression. We also discuss the immunologic and clinical implications of LOH in HLA on tumor clonal expansion and association with the cancer recurrence after treatment.
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Affiliation(s)
- Maria Antonia Garrido
- Servicio de Radiología, UGC de Radiología, Hospital Virgen de la Nieves, 18014 Granada, Spain;
| | - Francisco Perea
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
| | - Jose Ramon Vilchez
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
| | - Teresa Rodríguez
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
| | - Per Anderson
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
| | - Federico Garrido
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
- Departamento de Bioquímica, Biología Molecular III e Inmunología, Facultad de Medicina, Universidad de Granada, 18071 Granada, Spain
| | - Francisco Ruiz-Cabello
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (F.P.); (J.R.V.); (T.R.); (P.A.); (F.G.)
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
- Departamento de Bioquímica, Biología Molecular III e Inmunología, Facultad de Medicina, Universidad de Granada, 18071 Granada, Spain
- Correspondence: (F.R.-C.); (N.A.)
| | - Natalia Aptsiauri
- Instituto de Investigación Biosanitaria IBS.GRANADA, 18014 Granada, Spain
- Departamento de Bioquímica, Biología Molecular III e Inmunología, Facultad de Medicina, Universidad de Granada, 18071 Granada, Spain
- Correspondence: (F.R.-C.); (N.A.)
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Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression, T-Cell Exclusion and Stromal Changes. Int J Mol Sci 2021; 22:ijms22147248. [PMID: 34298868 PMCID: PMC8307653 DOI: 10.3390/ijms22147248] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 12/22/2022] Open
Abstract
Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.
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25
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Shklovskaya E, Rizos H. MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It. Int J Mol Sci 2021; 22:ijms22136741. [PMID: 34201655 PMCID: PMC8268865 DOI: 10.3390/ijms22136741] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/21/2022] Open
Abstract
It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.
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26
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Abstract
PURPOSE OF REVIEW Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome-associated carcinomas. RECENT FINDINGS Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome-associated cancers.
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Affiliation(s)
- Danielle M Pastor
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- NIH Hematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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27
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Beta2-microglobulin(B2M) in cancer immunotherapies: Biological function, resistance and remedy. Cancer Lett 2021; 517:96-104. [PMID: 34129878 DOI: 10.1016/j.canlet.2021.06.008] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 12/30/2022]
Abstract
Cancer immunotherapies have made much headway during the past decades. Techniques including the immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT) have harvested impressive efficacy and provided far-reaching tools for treating cancer patients. However, due to inadequate priming of the immune system, a certain subgroup of patients remains resistant to cancer immunotherapies during or after the treatment. β2-microglobulin (B2M) is an important subunit of major histocompatibility complex (MHC) class I which exerts substantive biological functions in tumorigenesis and immune control. Accumulating evidence has shown that alterations of B2M gene and B2M proteins contribute to poor reaction to cancer immunotherapies by dampening antigen presentation. Here, we discuss the basic biological functions of B2M, its distribution in a spectrum of cancers, and current understanding of its role in ICI, cancer vaccines and chimeric antigen receptor T cell (CAR-T) therapies. Furthermore, we summarize some promising therapeutic strategies to improve the efficacy inhibited by B2M defects.
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28
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Jongsma MLM, Neefjes J, Spaapen RM. Playing hide and seek: Tumor cells in control of MHC class I antigen presentation. Mol Immunol 2021; 136:36-44. [PMID: 34082257 DOI: 10.1016/j.molimm.2021.05.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 04/07/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022]
Abstract
MHC class I (MHC-I) molecules present a blueprint of the intracellular proteome to T cells allowing them to control infection or malignant transformation. As a response, pathogens and tumor cells often downmodulate MHC-I mediated antigen presentation to escape from immune surveillance. Although the fundamental rules of antigen presentation are known in detail, the players in this system are not saturated and new modules of regulation have recently been uncovered. Here, we update the understanding of antigen presentation by MHC-I molecules and how this can be exploited by tumors to prevent exposure of the intracellular proteome. This knowledge can provide new ways to improve immune responses against tumors and pathogens.
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Affiliation(s)
- M L M Jongsma
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - J Neefjes
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - R M Spaapen
- Department of Immunopathology, Sanquin Research, Amsterdam, the Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands.
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29
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Algarra I, Garrido F, Garcia-Lora AM. MHC heterogeneity and response of metastases to immunotherapy. Cancer Metastasis Rev 2021; 40:501-517. [PMID: 33860434 DOI: 10.1007/s10555-021-09964-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/06/2021] [Indexed: 01/05/2023]
Abstract
In recent years, immunotherapy has proven to be an effective treatment against cancer. Cytotoxic T lymphocytes perform an important role in this anti-tumor immune response, recognizing cancer cells as foreign, through the presentation of tumor antigens by MHC class I molecules. However, tumors and metastases develop escape mechanisms for evading this immunosurveillance and may lose the expression of these polymorphic molecules to become invisible to cytotoxic T lymphocytes. In other situations, they may maintain MHC class I expression and promote immunosuppression of cytotoxic T lymphocytes. Therefore, the analysis of the expression of MHC class I molecules in tumors and metastases is important to elucidate these escape mechanisms. Moreover, it is necessary to determine the molecular mechanisms involved in these alterations to reverse them and recover the expression of MHC class I molecules on tumor cells. This review discusses the role and regulation of MHC class I expression in tumor progression. We focus on altered MHC class I phenotypes present in tumors and metastases, as well as the molecular mechanisms responsible for MHC-I alterations, emphasizing the mechanisms of recovery of the MHC class I molecules expression on cancer cells. The individualized study of the HLA class I phenotype of the tumor and the metastases of each patient will allow choosing the most appropriate immunotherapy treatment based on a personalized medicine.
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Affiliation(s)
- Ignacio Algarra
- Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain
| | - Federico Garrido
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014, Granada, Spain.,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.,Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain
| | - Angel M Garcia-Lora
- Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. de las Fuerzas Armadas 2, 18014, Granada, Spain. .,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain. .,Unidad de Biobanco, Hospital Universitario Virgen de las Nieves, Granada, Spain.
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30
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Investigating T Cell Immunity in Cancer: Achievements and Prospects. Int J Mol Sci 2021; 22:ijms22062907. [PMID: 33809369 PMCID: PMC7999898 DOI: 10.3390/ijms22062907] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/21/2022] Open
Abstract
T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8+ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.
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31
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Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front Immunol 2021; 12:636568. [PMID: 33767702 PMCID: PMC7986854 DOI: 10.3389/fimmu.2021.636568] [Citation(s) in RCA: 561] [Impact Index Per Article: 140.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/05/2021] [Indexed: 02/03/2023] Open
Abstract
Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.
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32
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HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy. Cell Mol Immunol 2021; 18:556-565. [PMID: 33473191 PMCID: PMC8027055 DOI: 10.1038/s41423-021-00634-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/23/2020] [Indexed: 01/30/2023] Open
Abstract
T cell-mediated immune therapies have emerged as a promising treatment modality in different malignancies including colorectal cancer (CRC). However, only a fraction of patients currently respond to treatment. Understanding the lack of responses and finding biomarkers with predictive value is of great importance. There is evidence that CRC is a heterogeneous disease and several classification systems have been proposed that are based on genomic instability, immune cell infiltration, stromal content and molecular subtypes of gene expression. Human leukocyte antigen class I (HLA-I) plays a pivotal role in presenting processed antigens to T lymphocytes, including tumour antigens. These molecules are frequently lost in different types of cancers, including CRC, resulting in tumour immune escape from cytotoxic T lymphocytes during the natural history of cancer development. The aim of this review is to (i) summarize the prevalence and molecular mechanisms behind HLA-I loss in CRC, (ii) discuss HLA-I expression/loss in the context of the newly identified CRC molecular subtypes, (iii) analyze the HLA-I phenotypes of CRC metastases disseminated via blood or the lymphatic system, (iv) discuss strategies to recover/circumvent HLA-I expression/loss and finally (v) review the role of HLA class II (HLA-II) in CRC prognosis.
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Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in Gastric Cancer: Between lights and shadows. Cancer Treat Rev 2021; 95:102175. [PMID: 33721595 DOI: 10.1016/j.ctrv.2021.102175] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022]
Abstract
Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA and ACRG classifications, the microsatellite instable (MSI) group represents a significant subset of GCs and is currently in the limelight of many researches due to its favorable survival outcome in resectable stages compared to microsatellite stable tumors. MSI GCs hypermutated phenotype triggers immunosurveillance, making this molecular subgroup a promising candidate for immune checkpoint inhibitors treatment. Conversely, conflicting outcomes have been reported in chemotherapy settings. Due to the clinical relevance of these observations, in this review we report and discuss the molecular, pathological, prognostic, and predictive features of MSI gastric tumors.
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Affiliation(s)
- Elisabetta Puliga
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
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Catanese S, Lordick F. Targeted and immunotherapy in the era of personalised gastric cancer treatment. Best Pract Res Clin Gastroenterol 2021; 50-51:101738. [PMID: 33975679 DOI: 10.1016/j.bpg.2021.101738] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/16/2021] [Accepted: 02/19/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer is a major cause of cancer-related morbidity and mortality worldwide. Advances in targeted medical treatment were scarce in the past and challenged by the marked spatial and temporal biological heterogeneity of gastric cancer. Recent molecular profiling studies have increased our understanding of genetic and epigenetic drivers, leading to better patient selection for drug development. Beyond that, immune-related biomarkers were identified, paving the way for future effective immunotherapy. We systematically reviewed articles from PubMed of the past 10 years, and abstracts from annual meetings of ESMO, ASCO and AACR to summarise the current knowledge about targeted and immunotherapy and outline pathways to future personalised therapy of gastric cancer.
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Affiliation(s)
- Silvia Catanese
- Unit of Medical Oncology, Department of Oncology, University of Pisa, Pisa, Italy
| | - Florian Lordick
- Department of Oncology, Gastroenterology, Hepatology, Pulmonology, and Infectious Diseases, University Cancer Centre Leipzig (UCCL), Leipzig University Medical Centre, Leipzig, Germany.
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McWilliam HEG, Salio M. Understanding and modulating the MR1 metabolite antigen presentation pathway. Mol Immunol 2020; 129:121-126. [PMID: 33293099 DOI: 10.1016/j.molimm.2020.11.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 11/24/2020] [Indexed: 10/22/2022]
Abstract
The MHC class I-related protein, MR1, presents small metabolite antigens to an unusual subset of innate-like T cells. Herein, we highlight recent progress in our understanding of MR1's unique antigen presenting pathway, with features of both MHC class I and class II antigen presentation, as highlighted during the EMBO Workshop: CD1-MR1, Beyond MHC-restricted lymphocytes, Oxford, 2019. There is increasing evidence for a role of MR1 restricted T cells in several immune contexts, from cancer to autoimmunity and infections, and therapeutic harnessing of this important biological axis through generation of agonist and antagonist MR1 ligands requires a thorough understanding of the molecular mechanisms of MR1-dependent antigen presentation.
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Affiliation(s)
- Hamish E G McWilliam
- Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC, 3010, Australia.
| | - Mariolina Salio
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
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Sabbatino F, Liguori L, Polcaro G, Salvato I, Caramori G, Salzano FA, Casolaro V, Stellato C, Dal Col J, Pepe S. Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients. Int J Mol Sci 2020; 21:ijms21197295. [PMID: 33023239 PMCID: PMC7582904 DOI: 10.3390/ijms21197295] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/26/2020] [Accepted: 09/29/2020] [Indexed: 12/11/2022] Open
Abstract
Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients.
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Affiliation(s)
- Francesco Sabbatino
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
- Oncology Unit, AOU San Giovanni di Dio e Ruggi D’Aragona, 84131 Salerno, Italy
| | - Luigi Liguori
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy;
| | - Giovanna Polcaro
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
| | - Ilaria Salvato
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
- Pulmonary Unit, Department of Biomedical Sciences, Dentistry, Morphological and Functional Imaging (BIOMORF), University of Messina, 98125 Messina, Italy;
| | - Gaetano Caramori
- Pulmonary Unit, Department of Biomedical Sciences, Dentistry, Morphological and Functional Imaging (BIOMORF), University of Messina, 98125 Messina, Italy;
| | - Francesco A. Salzano
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
| | - Vincenzo Casolaro
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
| | - Cristiana Stellato
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
| | - Jessica Dal Col
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
- Correspondence: ; Tel.: +39-08996-5210
| | - Stefano Pepe
- Department of Medicine, Surgery and Dentistry ’Scuola Medica Salernitana’, University of Salerno, 84081 Baronissi, Salerno, Italy; (F.S.); (G.P.); (I.S.); (F.A.S.); (V.C.); (C.S.); (S.P.)
- Oncology Unit, AOU San Giovanni di Dio e Ruggi D’Aragona, 84131 Salerno, Italy
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Kok VC. Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer. Front Oncol 2020; 10:268. [PMID: 32185135 PMCID: PMC7058818 DOI: 10.3389/fonc.2020.00268] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 02/17/2020] [Indexed: 02/05/2023] Open
Abstract
Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.
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Affiliation(s)
- Victor C. Kok
- Department of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, Taiwan
- Department of Bioinformatics and Medical Engineering, Asia University Taiwan, Taichung, Taiwan
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Promotion on NLRC5 upregulating MHC-I expression by IFN-γ in MHC-I–deficient breast cancer cells. Immunol Res 2020; 67:497-504. [DOI: 10.1007/s12026-019-09111-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Garrido F, Aptsiauri N. Cancer immune escape: MHC expression in primary tumours versus metastases. Immunology 2019; 158:255-266. [PMID: 31509607 PMCID: PMC6856929 DOI: 10.1111/imm.13114] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/28/2019] [Accepted: 09/03/2019] [Indexed: 12/18/2022] Open
Abstract
Tumours can escape T-cell responses by losing major histocompatibility complex (MHC)/ human leucocyte antigen (HLA) class I molecules. In the early stages of cancer development, primary tumours are composed of homogeneous HLA class I-positive cancer cells. Subsequently, infiltration of the tumour by T cells generates a vast diversity of tumour clones with different MHC class I expressions. A Darwinian type of T-cell-mediated immune selection results in a tumour composed solely of MHC class I-negative cells. Metastatic colonization is a highly complex phenomenon in which T lymphocytes and natural killer cells play a major role. We have obtained evidence that the MHC class I phenotype of metastatic colonies can be highly diverse and is not necessarily the same as that of the primary tumour. The molecular mechanisms responsible for MHC/HLA class I alterations are an important determinant of the clinical response to cancer immunotherapy. Hence, immunotherapy can successfully up-regulate MHC/HLA class I expression if the alteration is reversible ('soft'), leading to T-cell-mediated tumour regression. In contrast, it cannot recover this expression if the alteration is irreversible ('hard'), when tumour cells escape T-cell-mediated destruction with subsequent cancer progression. This review summarizes clinical and experimental data on the complexity of immune escape mechanisms used by tumour cells to avoid T and natural killer cell responses. We also provide in-depth analysis of the nature of MHC/HLA class I changes during metastatic colonization and contribute evidence of the enormous diversity of MHC/HLA class I phenotypes that can be produced by tumour cells during this process.
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Affiliation(s)
- Federico Garrido
- Servicio de Analisis Clínicos e InmunologíaUGC Laboratorio ClínicoHospital Universitario Virgen de las NievesGranadaSpain
- Instituto de Investigación Biosanitaria ibs (A‐08)GranadaSpain
- Departamento de Bioquímica, Biología Molecular e Inmunología IIIFacultad de MedicinaUniversidad de GranadaGranadaSpain
| | - Natalia Aptsiauri
- Instituto de Investigación Biosanitaria ibs (A‐08)GranadaSpain
- Departamento de Bioquímica, Biología Molecular e Inmunología IIIFacultad de MedicinaUniversidad de GranadaGranadaSpain
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Yang Y, Nam GH, Kim GB, Kim YK, Kim IS. Intrinsic cancer vaccination. Adv Drug Deliv Rev 2019; 151-152:2-22. [PMID: 31132376 DOI: 10.1016/j.addr.2019.05.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/22/2019] [Accepted: 05/22/2019] [Indexed: 12/15/2022]
Abstract
Immunotherapy is revolutionizing the treatment of cancer, and the current immunotherapeutics have remarkably improved the outcomes for some cancer patients. However, we still need answers for patients with immunologically cold tumors that do not benefit from the current immunotherapy treatments. Here, we suggest a novel strategy that is based on using a very old and sophisticated system for cancer immunotherapy, namely "intrinsic cancer vaccination", which seeks to awaken our own immune system to activate tumor-specific T cells. To do this, we must take advantage of the genetic instability of cancer cells and the expression of cancer cell neoantigens to trigger immunity against cancer cells. It will be necessary to not only enhance the phagocytosis of cancer cells by antigen presenting cells but also induce immunogenic cancer cell death and the subsequent immunogenic clearance, cross-priming and generation of tumor-specific T cells. This strategy will allow us to avoid using known tumor-specific antigens, ex vivo manipulation or adoptive cell therapy; rather, we will efficiently present cancer cell neoantigens to our immune system and propagate the cancer-immunity cycle. This strategy simply follows the natural cycle of cancer-immunity from its very first step, and therefore could be combined with any other treatment modality to yield enhanced efficacy.
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Affiliation(s)
- Yoosoo Yang
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Gi-Hoon Nam
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Gi Beom Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Yoon Kyoung Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - In-San Kim
- Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
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Massari F, Nunno VD, Mollica V, Montironi R, Cheng L, Cimadamore A, Blanca A, Lopez-Beltran A. Immunotherapy in renal cell carcinoma from poverty to the spoiled of choice. Immunotherapy 2019; 11:1507-1521. [PMID: 31663411 DOI: 10.2217/imt-2019-0115] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Management of metastatic renal cell carcinoma has been enriched by the advent of new therapeutic compounds. The approval of new combination strategies between targeted agents and immune-checkpoint inhibitors as well as the administration of combinations between immune-checkpoint inhibitors has clearly demonstrated significant improvement toward patients' prognosis and other clinical outcomes. Due to the availability of different treatments, the choice between them may be a difficult issue in our clinical practice. We have summarized current knowledge about available treatments focusing on criteria, which may help clinicians to make decisions.
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Affiliation(s)
| | | | - Veronica Mollica
- Division of Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Rodolfo Montironi
- Section of Pathological Anatomy, United Hospital, School of Medicine, Polytechnic University of the Marche Region, Ancona, Italy
| | - Liang Cheng
- Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alessia Cimadamore
- Section of Pathological Anatomy, United Hospital, School of Medicine, Polytechnic University of the Marche Region, Ancona, Italy
| | - Ana Blanca
- Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Antonio Lopez-Beltran
- Department of Pathology & Surgery, Faculty of Medicine, Cordoba University, Cordoba, Spain
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Bogomiakova ME, Eremeev AV, Lagarkova MA. At Home among Strangers: Is It Possible to Create Hypoimmunogenic Pluripotent Stem Cell Lines? Mol Biol 2019. [DOI: 10.1134/s0026893319050042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Barrow P, Richman SD, Wallace AJ, Handley K, Hutchins GGA, Kerr D, Magill L, Evans DG, Gray R, Quirke P, Hill J. Confirmation that somatic mutations of beta-2 microglobulin correlate with a lack of recurrence in a subset of stage II mismatch repair deficient colorectal cancers from the QUASAR trial. Histopathology 2019; 75:236-246. [PMID: 31062389 PMCID: PMC6772160 DOI: 10.1111/his.13895] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/16/2019] [Accepted: 05/01/2019] [Indexed: 01/05/2023]
Abstract
Aims Beta2‐microglobulin (B2M) forms part of the HLA class I complex and plays a role in metastatic biology. B2M mutations occur frequently in mismatch repair‐deficient colorectal cancer (dMMR CRC), with limited data suggesting they may protect against recurrence. Our experimental study tested this hypothesis by investigating B2M mutation status and B2M protein expression and recurrence in patients in the stage II QUASAR clinical trial. Methods and results Sanger sequencing was performed for the three coding exons of B2M on 121 dMMR and a subsample of 108 pMMR tumours; 52 with recurrence and 56 without. B2M protein expression was assessed by immunohistochemistry. Mutation status and protein expression were correlated with recurrence and compared to proficient mismatch repair (pMMR) CRCs. Deleterious B2M mutations were detected in 39 of 121 (32%) dMMR tumours. Five contained missense B2M‐variants of unknown significance, so were excluded from further analyses. With median follow‐up of 7.4 years, none of the 39 B2M‐mutant tumours recurred, compared with 14 of 77 (18%) B2M‐wild‐type tumours (P = 0.005); six at local and eight at distant sites. Sensitivity and specificity of IHC in detecting B2M mutations was 87 and 71%, respectively. Significantly (P < 0.0001) fewer (three of 104, 2.9%) of the 108 pMMR CRCs demonstrated deleterious B2M mutations. One pMMR tumour, containing a frameshift mutation, later recurred. Conclusion B2M mutations were detected in nearly one‐third of dMMR cancers, none of which recurred. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC. The mechanism of protection against recurrence and whether this protection extends to stage III disease remains unclear.
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Affiliation(s)
- Paul Barrow
- Department of Surgery, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Trust, Manchester, UK
| | - Susan D Richman
- Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK
| | - Andrew J Wallace
- Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Hospitals NHS Trust, Manchester, UK
| | - Kelly Handley
- Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - Gordon G A Hutchins
- Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK
| | - David Kerr
- Cancer Medicine, University of Oxford, Oxford, UK
| | - Laura Magill
- Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Hospitals NHS Trust, Manchester, UK
| | | | - Phil Quirke
- Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK
| | - James Hill
- Department of Surgery, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Trust, Manchester, UK
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Resistance to Systemic Agents in Renal Cell Carcinoma Predict and Overcome Genomic Strategies Adopted by Tumor. Cancers (Basel) 2019; 11:cancers11060830. [PMID: 31207938 PMCID: PMC6627706 DOI: 10.3390/cancers11060830] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/25/2019] [Accepted: 06/11/2019] [Indexed: 12/15/2022] Open
Abstract
The development of new systemic agents has led us into a "golden era" of management of metastatic renal cell carcinoma (RCC). Certainly, the approval of immune-checkpoint inhibitors and the combination of these with targeted compounds has irreversibly changed clinical scenarios. A deeper knowledge of the molecular mechanisms that correlate with tumor development and progression has made this revolution possible. In this amazing era, novel challenges are awaiting us in the clinical management of metastatic RCC. Of these, the development of reliable criteria which are able to predict tumor response to treatment or primary and acquired resistance to systemic treatments still remain an unmet clinical need. Thanks to the availability of data provided by studies evaluating genomic assessments of the disease, this goal may no longer be out of reach. In this review, we summarize current knowledge about genomic alterations related to primary and secondary resistance to target therapy and immune-checkpoint inhibitors in RCC.
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Total HLA Class I Antigen Loss with the Downregulation of Antigen-Processing Machinery Components in Two Newly Established Sarcomatoid Hepatocellular Carcinoma Cell Lines. J Immunol Res 2019; 2018:8363265. [PMID: 30648121 PMCID: PMC6311956 DOI: 10.1155/2018/8363265] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 06/19/2018] [Accepted: 08/02/2018] [Indexed: 02/06/2023] Open
Abstract
Limited information is currently available concerning HLA class I antigen abnormalities in sarcomatoid hepatocellular carcinoma (sHCC). Here, we have analyzed the growth characteristics and HLA class I antigen status of four sHCC cell lines (sHCC29, sHCC63, sHCC74, and SAR-HCV); the first three were newly established in this study. Among the four, sHCC29 showed the highest growth rate in vitro and tumorigenicity in NOD-SCID mice. Unlike sHCC74 and SAR-HCV, both sHCC29 and sHCC63 had no detectable surface HLA class I antigen expression, alongside undetected intracellular β2-microglobulin (β2m) and marked HLA class I heavy chain and selective antigen-processing machinery (APM) component downregulation. The loss of β2m in sHCC29 and sHCC63 was caused by a >49 kb deletion across the B2M locus, while their downregulation of APM components was transcriptional, reversible by IFN-γ only in several components. β2m was also undetected in the primary HCC lesions of the patients involved, indicating its in vivo relevance. We report for the first time HLA class I antigen loss with underlying B2M gene deficiency and APM defects in 50% (2 of 4) of the sHCC cell lines tested. These findings may have implications for a proper design of T cell immunotherapy for the treatment of sHCC patients.
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Abstract
In this chapter I describe Tumour Immune Escape mechanisms associated with MHC/HLA class I loss in human and experimental tumours. Different altered HLA class-I phenotypes can be observed that are produced by different molecular mechanisms. Experimental and histological evidences are summarized indicating that at the early stages of tumour development there is an enormous variety of tumour clones with different MHC class I expression patterns. This phase is followed by a strong T cell mediated immune-selection of MHC/HLA class-I negative tumour cells in the primary tumour lesion. This transition period results in a formation of a tumour composed only of HLA-class I negative cells. An updated description of this process observed in a large variety of human tumors is included. In the second section I focus on MHC/HLA class I alterations observed in mouse and human metastases, and describe the generation of different tumor cell clones with altered MHC class I phenotypes, which could be similar or different from the original tumor clone. The biological and immunological relevance of these observations is discussed. Finally, the interesting phenomenon of metastatic dormancy is analyzed in association with a particular MHC class I negative tumor phenotype.
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Affiliation(s)
- Federico Garrido
- Departamento de Analisis Clinicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Facultad de Medicina, Universidad de Granada, Granada, Spain
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Garrido F. HLA Class-I Expression and Cancer Immunotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1151:79-90. [PMID: 31140107 DOI: 10.1007/978-3-030-17864-2_3] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The impact of HLA class I loss in cancer immunotherapy is carefully analyzed. Why some metastatic lesions regress and other progress after immunotherapy? Are T lymphocytes responsible for tumour rejection and how these responses can be boosted? These questions are discussed in the context of the molecular mechanisms responsible for MHC/HLA class I alterations. If the metastatic tumour cells harbor "irreversible/hard" HLA lesions, they will escape and kill the host. In contrast, if the molecular lesion is "reversible/soft", tumor cells can potentially recover HLA-class I expression and can finally be destroyed. These important new concepts are integrated together and gain a great importance in the new era of "immune checkpoint antibodies". Finally, the ability to recover HLA-I expression in tumours harboring "structural-irreversible-hard" genetic lesions is seen as a challenge for the future investigation.
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Affiliation(s)
- Federico Garrido
- Departamento de Analisis Clinicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Facultad de Medicina, Universidad de Granada, Granada, Spain
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Montes P, Kerick M, Bernal M, Hernández F, Jiménez P, Garrido P, Márquez A, Jurado M, Martin J, Garrido F, Ruiz-Cabello F. Genomic loss of HLA alleles may affect the clinical outcome in low-risk myelodysplastic syndrome patients. Oncotarget 2018; 9:36929-36944. [PMID: 30651926 PMCID: PMC6319343 DOI: 10.18632/oncotarget.26405] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/24/2018] [Indexed: 12/31/2022] Open
Abstract
The Revised International Prognostic Score and some somatic mutations in myelodysplastic syndrome (MDS) are independently associated with transformation to acute myeloid leukemia (AML). Immunity has also been implicated in the pathogenesis of MDS, although the underlying mechanism remains unclear. We performed a SNP array on chromosome 6 in CD34+ purified blasts from 19 patients diagnosed with advanced MDS and 8 patients with other myeloid malignancies to evaluate the presence of loss of heterozygosity (LOH) in HLA and its impact on disease progression. Three patients had acquired copy-neutral LOH (CN-LOH) on 6p arms, which may disrupt antigen presentation and act as a mechanism for immune system evasion. Interestingly, these patients had previously been classified at low risk of AML progression, and the poor outcome cannot be explained by the acquisition of adverse mutations. LOH HLA was not detected in the remaining 24 patients, who all had adverse risk factors. In summary, the clinical outcome of patients with advanced MDS might be influenced by HLA allelic loss, wich allows subclonal expansions to evade cytotoxic-T and NK cell attack. CN-LOH HLA may therefore be a factor favoring MDS progression to AML independently of the somatic tumor mutation load.
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Affiliation(s)
- Paola Montes
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Martin Kerick
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
| | - Mónica Bernal
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Francisca Hernández
- UGC de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Pilar Jiménez
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Pilar Garrido
- UGC de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Ana Márquez
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
| | - Manuel Jurado
- UGC de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Javier Martin
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain
| | - Federico Garrido
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain.,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.,Departamento Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain
| | - Francisco Ruiz-Cabello
- Servicio de Análisis Clínicos e Inmunología, UGC de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain.,Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain.,Departamento Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain
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Lybaert L, Vermaelen K, De Geest BG, Nuhn L. Immunoengineering through cancer vaccines – A personalized and multi-step vaccine approach towards precise cancer immunity. J Control Release 2018; 289:125-145. [DOI: 10.1016/j.jconrel.2018.09.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023]
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Teng H, Gao R, Qin N, Jiang X, Ren M, Wang Y, Wu S, Li N, Zhao J, Qin H. Identification of recurrent and novel mutations by whole‑genome sequencing of colorectal tumors from the Han population in Shanghai, eastern China. Mol Med Rep 2018; 18:5361-5370. [PMID: 30365144 PMCID: PMC6236297 DOI: 10.3892/mmr.2018.9563] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022] Open
Abstract
Previous studies have identified recurrent oncogenic mutations in colorectal cancer (CRC), but there is limited CRC genomic data from the Chinese Han population. Whole‑genome sequencing was performed on 10 primary CRC tumors and matched adjacent normal tissues from patients from the Han population in Shanghai, at an average of 27.8x and 27.9x coverage, respectively. In the 10 tumor samples, 32 significant somatic mutated genes were identified, 13 of which were also reported as CRC mutations in The Cancer Genome Atlas Network. All the mutated genes were enriched in functions associated with channel activity, which has rarely been reported in previous studies investigating CRC. Furthermore, 21 chromosomal rearrangements were detected and 4 rearrangements encoded predicted in‑frame fusion proteins, including a fusion of phosphorylase kinase regulatory subunit b and NOTCH2 demonstrated in 2 out of 10 tumors. Chromosome 8 was amplified in 1 tumor and chromosome 20 was amplified in 2 out of 10 CRC patients. The present study produced a genomic mutation profile of CRC, which provides a valuable resource for further insight into the mutations that characterize CRC in patients from the Han population in Shanghai, eastern China.
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Affiliation(s)
- Hongfei Teng
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Renyuan Gao
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Nan Qin
- Department of Gut Microbiota Diagnosis and Treatment, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xun Jiang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Min Ren
- Department of Medicine, Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 201204, P.R. China
| | - Yu Wang
- Department of Medicine, Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 201204, P.R. China
| | - Shouxin Wu
- Department of Medicine, Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 201204, P.R. China
| | - Ning Li
- Department of Gut Microbiota Diagnosis and Treatment, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Jiangman Zhao
- Department of Medicine, Biotecan Medical Diagnostics Co., Ltd., Zhangjiang Center for Translational Medicine, Shanghai 201204, P.R. China
| | - Huanlong Qin
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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