Immune checkpoint signaling and cancer immunotherapy

Cell Research, Journal Year: 2020, Volume and Issue: 30(8), P. 660 - 669

Published: May 28, 2020

Abstract Immune checkpoint blockade therapy has become a major weapon in fighting cancer. Antibody drugs, such as anti-PD-1 and anti-PD-L1, demonstrate obvious advantages broad applicability across cancer types durable clinical response when treatment is effective. However, the overall rates are still unsatisfying, especially for cancers with low mutational burden. Moreover, adverse effects, autoimmune symptoms tumor hyperprogression, present significant downside some applications. These challenges reflect urgent need to fully understand basic biology of immune checkpoints. In this review, we discuss regulation signaling at multiple levels provide an overview our current understanding biology. Topics include surface expression known proteins via delivery, internalization, recycling, degradation. Upon reaching surface, checkpoints engage both conventional trans also cis interactions ligands induce regulate responses. Novel therapeutic strategies targeting these pathways addition classical have recently emerged been tested preclinical models, providing new avenues developing next-generation immunotherapies.

Language: Английский

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Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

Cancer Science, Journal Year: 2019, Volume and Issue: 110(7), P. 2080 - 2089

Published: May 18, 2019

Regulatory T (Treg) cells suppress abnormal/excessive immune responses to self- and nonself-antigens maintain homeostasis. In tumor immunity, Treg are involved in development progression by inhibiting antitumor immunity. There several cell suppressive mechanisms: inhibition of costimulatory signals CD80 CD86 expressed dendritic through cytotoxic T-lymphocyte antigen-4, interleukin (IL)-2 consumption high-affinity IL-2 receptors with high CD25 (IL-2 receptor α-chain) expression, secretion inhibitory cytokines, metabolic modulation tryptophan adenosine, direct killing effector cells. Infiltration into the microenvironment (TME) occurs multiple murine human tumors. chemoattracted TME chemokine gradients such as CCR4-CCL17/22, CCR8-CCL1, CCR10-CCL28, CXCR3-CCL9/10/11. then activated inhibit responses. A infiltration is associated poor survival various types cancer. Therefore, strategies deplete control functions increase urgently required cancer immunotherapy field. Various molecules that highly cells, checkpoint molecules, receptors, metabolites, have been targeted Abs or small but additional needed fine-tune optimize for augmenting effects restricted while avoiding systemic autoimmunity. Here, we provide a brief synopsis these how they can be controlled achieve therapeutic outcomes.

Language: Английский

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Regulatory T Cells and Human Disease

Annual Review of Immunology, Journal Year: 2020, Volume and Issue: 38(1), P. 541 - 566

Published: Feb. 4, 2020

Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in nucleus and CD25 CTLA-4 on cell surface, are a functionally distinct subpopulation actively engaged maintenance of immunological self-tolerance homeostasis. Recent studies have facilitated our understanding cellular molecular basis their generation, function, phenotypic functional stability, adaptability. It is under investigation humans how or numerical Treg anomalies, whether genetically determined environmentally induced, contribute to diseases such as autoimmune diseases. Also being addressed Tregs can be targeted control physiological pathological immune responses, for example, by depleting them enhance tumor immunity expanding treat This review discusses current immunobiology normal disease states, with perspective realization Treg-targeting therapies clinic.

Language: Английский

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Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: July 17, 2020

Abstract Regulatory T cells (Tregs) characterized by the expression of master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot field. However, Tregs are also essential for maintenance tolerance body share many molecular signalling pathways with conventional cells, including cytotoxic primary mediators tumour immunity. Hence, inability to specifically target neutralize microenvironment without globally compromising self-tolerance poses significant challenge. Here, we review recent advances characterizing tumour-infiltrating focus on functional roles costimulatory inhibitory receptors Tregs, evaluate their potential as clinical targets, systematically summarize treatment strategies. Also, propose modalities integrate our increasing knowledge phenotype function rational design checkpoint inhibitor-based combination therapies. Finally, possible strategies that can be used develop Treg-targeted

Language: Английский

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Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)

Journal of Clinical Oncology, Journal Year: 2020, Volume and Issue: 38(18), P. 2053 - 2061

Published: April 28, 2020

This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer.Enrolled patients received in dose-finding part to estimate the maximum tolerated dose. Additional were enrolled dose-expansion part. Regorafenib 80-160 mg was administered once daily 21 days on/7 off with 3 mg/kg every 2 weeks. The primary end point dose-limiting toxicity (DLT) during first 4 weeks recommended dose.Fifty (25 each cancer) enrolled. All had ≥ previous lines chemotherapy, including anti-angiogenetic inhibitors 96% patients. Seven cancer previously been treated immune checkpoint inhibitors. One patient microsatellite instability-high cancer, whereas remaining stable or mismatch repair-proficient tumors. Three DLTs (grade colonic perforation, maculopapular rash, proteinuria) observed 160 mg; none 80 120 mg. During part, dose reduced from because frequent rash. common grade treatment-related adverse events rash (12%), proteinuria palmar-plantar erythrodysesthesia (10%). Objective tumor response 20 (40%), 11 (44%) 9 (36%). Median progression-free survival 5.6 7.9 months respectively.The combination manageable safety profile encouraging antitumor activity which warrants additional investigations larger cohorts.

Language: Английский

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Tumor-infiltrating lymphocytes in the immunotherapy era

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 18(4), P. 842 - 859

Published: Nov. 2, 2020

Language: Английский

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The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies

Nature Immunology, Journal Year: 2020, Volume and Issue: 21(11), P. 1346 - 1358

Published: Aug. 31, 2020

Language: Английский

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Intratumoral heterogeneity in cancer progression and response to immunotherapy

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(2), P. 212 - 224

Published: Feb. 1, 2021

Language: Английский

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Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(2), P. 201 - 218.e9

Published: Jan. 28, 2022

Language: Английский

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The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies

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

Published: May 7, 2020

Tumor cells constantly interact with their microenvironment, which comprises a variety of immune together endothelial and fibroblasts. The composition the tumor microenvironment (TME) has been shown to influence response checkpoint blockade (ICB). ICB takes advantage cell infiltration in reinvigorate an efficacious antitumoral response. In addition intrinsic biomarkers, increasing data pinpoint importance TME guiding patient selection combination therapies. Here, we review recent efforts determining how various components can resistance ICB. Although large body evidence points extent functional orientation T infiltrate as important therapy response, studies also confirm role for other TME, such B cells, myeloid lineage cancer-associated fibroblasts vasculature. If ultimate goal curative cancer therapies is induce long-term memory may positively or negatively modulate induction efficient antitumor immunity. emergence novel high-throughput methods analyzing including transcriptomics, allowed tremendous developments field, expansion cohorts identification TME-based markers Together, these open possibility selecting patients that are likely respond specific therapies, pave way personalized medicine oncology.

Language: Английский

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