CD8+ T cell differentiation and dysfunction in cancer

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(4), P. 209 - 223

Published: July 12, 2021

Language: Английский

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Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Aug. 11, 2020

Abstract Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2 (IDO/TDO) promotes immunosuppression across different cancer types. The metabolite L-Kynurenine (Kyn) interacts with ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive generation of Tregs tolerogenic myeloid cells PD-1 up-regulation in CD8 + T cells. Here, we show that AHR pathway is selectively active IDO/TDO-overexpressing tumors associated resistance immune checkpoint inhibitors. We demonstrate IDO-Kyn-AHR-mediated depends on an interplay between tumor-associated macrophages, which can be reversed inhibition. Selective blockade delays progression tumors, its efficacy improved combination blockade. Our findings suggest blocking IDO/TDO expressing would overcome limitation single IDO or TDO targeting agents constitutes a personalized approach immunotherapy, particularly

Language: Английский

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Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons

Cell Communication and Signaling, Journal Year: 2022, Volume and Issue: 20(1)

Published: April 7, 2022

Abstract The main breakthrough in tumor immunotherapy was the discovery of immune checkpoint (IC) proteins, which act as a potent suppressor system by myriad mechanisms. After that, scientists focused on molecules mainly. Thereby, much effort spent to progress novel strategies for suppressing these inhibitory axes, resulting evolution inhibitors (ICIs). Then, ICIs have become promising approach and shaped paradigm shift immunotherapies. CTLA-4 plays an influential role attenuation induction naïve memory T cells engagement with its responding ligands like B7-1 (CD80) B7-2 (CD86). Besides, PD-1 is predominantly implicated adjusting cell function peripheral tissues through interaction programmed death-ligand 1 (PD-L1) PD-L2. Given their suppressive effects anti-tumor immunity, it has firmly been documented that based therapies can be practical rational therapeutic approaches treat cancer patients. Nonetheless, inherent or acquired resistance ICI some treatment-related toxicities restrict application clinic. current review will deliver comprehensive overview human tumors alone combination other modalities support more desired outcomes lower

Language: Английский

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Gut microbiome and its role in colorectal cancer

BMC Cancer, Journal Year: 2021, Volume and Issue: 21(1)

Published: Dec. 11, 2021

Colorectal cancer (CRC) is still one of the most common types in world, and gut microbiome plays an important role its development. The involved carcinogenesis, formation progression CRC as well response to different systemic therapies. composition bacterial strains influence geography, race, sex, diet on serve information for screening, early detection prediction treatment outcome CRC.Microbiome modulation prospective new strategies medicine improve health individuals. Therefore, future research clinical trials oncology patients are warranted determine efficacy treatments CRC, minimize adverse effects increase survival rates.

Language: Английский

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Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Sept. 10, 2020

Recent breakthroughs in tumor immunotherapy such as immune checkpoint blockade (ICB) antibodies, have demonstrated the capacity of system to fight cancer a number malignancies melanoma and lung cancer. The numbers, localization phenotypes tumor-infiltrating lymphocytes (TIL) are not only predictive response but also key modulators disease progression. In this review, we focus on TIL profiling cutaneous using histopathological approaches highlight observed prognostic value primary subsets. quantification formalin-fixed samples ranges from visual scoring lymphocytic infiltrates H&E multiplex immunohistochemistry immunofluorescence followed by enumeration image analysis software. Nevertheless, current literature primarily relies upon single marker analyses major lymphocyte subsets conventional T cells (CD3, CD4, CD8), regulatory (FOXP3) B (CD20). We review studies associations between patient survival. cover recent findings with respect existence ectopic lymphoid aggregates found TME which termed tertiary structures (TLS) generally positive feature. addition their significance, various sub-populations has been reported predict patient's ICB. Thus, potential patients receiving ICB discussed. Finally, describe recently developed state-of-the-art for infiltrating digital pathology algorithms (e.g. Immunoscore) proteomics-based immunophenotyping platforms imaging mass cytometry). Translating these novel technologies revolutionize immunopathology leading altering our understanding immunology dramatically improving outcomes patients.

Language: Английский

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Resistance to Checkpoint Inhibition in Cancer Immunotherapy

Translational Oncology, Journal Year: 2020, Volume and Issue: 13(3), P. 100738 - 100738

Published: Feb. 27, 2020

The interaction of the host immune system with tumor cells in tissue microenvironment is essential understanding immunity and development successful cancer immunotherapy. presence lymphocytes tumors highly correlated an improved outcome. T have a set cell surface receptors termed checkpoints that when activated suppress function. Upregulation checkpoint such as programmed death 1 (PD-1) cytotoxic lymphocyte associated protein 4 (CTLA-4) occurs during activation effort to prevent damage from excessive response. Immune inhibitors allow adaptive respond more effectively. There has been clinical success different types blocking PD-1 CTLA. However, relapse occurred. innate acquired/therapy induced resistance treatment encountered. Aberrant cellular signal transduction major contributing factor Combination therapies other co-inhibitory TIM-3, LAG3 VISTA are currently being tested overcome Expression TIM-3 blockade combined demonstrated responses preclinical models. potential increase responsiveness T-cells tumors. Furthermore, were found express had increased rate growth due suppression. growing inhibitory checkpoints' ligand biology, signaling mechanisms, T-cell suppression continues fuel advancements design, testing, approval agents block molecules. Our review seeks bridge fundamental regulatory mechanisms across great importance We will summarize biology molecules, highlight effect individual inhibition anti-tumor therapies, outline literatures explore pathways.

Language: Английский

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Immunotherapy in Lung Cancer: Current Landscape and Future Directions

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 9, 2022

Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of biology led to development many effective targeted therapies as well immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in non-small cell (NSCLC) and are now being used first-line metastatic disease, consolidation therapy following chemoradiation unresectable locally advanced adjuvant surgical resection chemotherapy resectable disease. Despite these benefits, predicting who will respond ICIs proven be difficult there remains need discover new predictive immunotherapy biomarkers. Furthermore, resistance is frequent either because lack response or disease progression after an initial response. The utility small (SCLC) limited extensive stage combination with modest impact on overall survival. It thus important explore exploit additional targets reap full benefits cancer. Here, we summarize current state cancer, discuss novel targets, intersection between DNA repair defects

Language: Английский

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Acquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression

Seminars in Cancer Biology, Journal Year: 2019, Volume and Issue: 65, P. 13 - 27

Published: July 27, 2019

Language: Английский

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Neoadjuvant Chemoradiotherapy Combined with Atezolizumab for Resectable Esophageal Adenocarcinoma: A Single-arm Phase II Feasibility Trial (PERFECT)

Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 27(12), P. 3351 - 3359

Published: Jan. 27, 2021

The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated feasibility and efficacy of nCRT combined programmed-death ligand-1 (PD-L1) inhibition rEAC.Patients rEAC received according to regimen five cycles atezolizumab (1,200 mg). primary endpoint was administering in ≥75% patients. A propensity score-matched cohort used compare pathologic response, overall survival, progression-free survival. Exploratory biomarker analysis performed on repeated tumor biopsies.We enrolled 40 whom 85% all atezolizumab. Immune-related adverse events any grade were observed 6 total, 83% proceeded surgery. Reasons not undergoing surgery progression (n = 4), patient choice 2), death 1). complete response rate 25% (10/40). No statistically significant difference or survival found between cohort. Baseline expression an IFNγ signature higher responders compared nonresponders (P 0.043). On-treatment showed either a high number cytotoxic lymphocytes (CTL) transcriptional consistent immune checkpoints, low CTLs.Combining is feasible rEAC. On basis our exploratory study, future studies are necessary elucidate potential immunotherapy subgroups.See related commentary by Catenacci, p. 3269.

Language: Английский

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Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Nov. 5, 2020

Cancer immunotherapy with antibodies targeting the programmed cell death 1 protein (PD-1)/ ligand (PD-L1) axis have changed standard of care in multiple cancers. However, durable antitumor responses been observed only a minority patients, indicating presence other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against immune suppressive are needed enhance immunity and maximize clinical benefit cancer patients who resistant checkpoint inhibition. Preclinical studies identified abnormalities tumor microenvironment (TME) can thwart efficacy PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression TME by inducing abnormalities, suppressing antigen presentation effector cells, or augmenting activity regulatory T myeloid-derived suppressor tumor-associated macrophages. In turn, immunosuppressive cells angiogenesis, thereby creating vicious cycle suppressed VEGF-mediated suppression its negative impact on provide rationale combine anti-VEGF drugs normalize TME. A multitude trials initiated evaluate combinations antibody an variety Recently, positive results from five Phase III non-small lung (adenocarcinoma), renal carcinoma, hepatocellular carcinoma shown agents significantly improved outcomes compared respective standards care. Such approved health authorities now treatment options for cancer, carcinoma. plethora randomized similar currently ongoing. Here we discuss principle studied preclinical models part translational studies. We also data recently reported trials. Finally, how these concepts approaches be further incorporated into practice improve cancer.

Language: Английский

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