Cold and hot tumors: from molecular mechanisms to targeted therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 18, 2024

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment therapy, only a minority patients exhibit positive response to it. In with solid tumors, those who respond well typically demonstrate an active profile referred as "hot" (immune-inflamed) phenotype. On other hand, non-responsive may distinct "cold" (immune-desert) phenotype, differing from features tumors. Additionally, there is more nuanced "excluded" positioned between and categories, known type. Effective differentiation understanding intrinsic factors, characteristics, TME, external factors are critical for predicting results. It widely accepted that therapy exerts profound effect on limited efficacy against or "altered" necessitating combinations therapeutic modalities enhance cell infiltration into tissue convert tumors ones. Therefore, aligning traits this review systematically delineates respective influencing extensively discusses varied approaches drug targets based assess efficacy.

Language: Английский

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Regulatory T cells in immune checkpoint blockade antitumor therapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Nov. 8, 2024

Regulatory T cells (Tregs), an essential component of the human immune system, are a heterogeneous group lymphocytes with ability to suppress responses and maintain homeostasis. Recent evidence indicates that Tregs may impair antitumor immunity facilitate cancer progression by weakening functions effector (Teffs). Consequently, targeting eliminate them from tumor microenvironments improve Teffs' activity could emerge as effective strategy for immunotherapy. This review outlines biology Tregs, detailing their origins, classification, crucial markers. Our focus lies on complex role in cancer's development, treatment, particularly suppressive upon via multiple mechanisms. We delve into Tregs' involvement checkpoint blockade (ICB) therapy, dual effect immunotherapy potential biomarkers ICB therapy effectiveness. also summarize advances therapies adjust optimize which be devising innovative treatment strategies.

Language: Английский

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IMbrave152/SKYSCRAPER-14: a Phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma

Future Oncology, Journal Year: 2024, Volume and Issue: 20(28), P. 2049 - 2057

Published: June 10, 2024

Atezolizumab plus bevacizumab is a standard of care, first-line therapy for advanced hepatocellular carcinoma (HCC). Myeloid and T regulatory cells are key immunosuppressive cell types within the hepatic tumor microenvironment associated with clinical resistance to atezolizumab HCC overall poor prognosis. Therapeutic targeting TIGIT, which highly expressed in these cells, tiragolumab may overcome environment improve benefit, hypothesis supported by positive efficacy signals Phase Ib/II MORPHEUS-Liver study. This paper describes rationale design IMbrave152/SKYSCRAPER-14, randomized, double-blind, placebo-controlled III study comparing or placebo patients no prior systemic treatment.

Language: Английский

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Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 906 - 906

Published: March 6, 2025

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in subset patients. However, with fewer than 50% patients achieving significant benefits, there is critical need to expand therapeutic strategies. This review explores emerging targets immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight biological basis CD8 T cell exhaustion shaping antitumor response. Novel approaches additional inhibitory receptors (IR) are discussed, focus on their distinct mechanisms action combinatory potential existing therapies. Despite advancements, challenges remain overcoming resistance optimizing patient selection. underscores importance dual blockade innovative bispecific antibody engineering maximize outcomes for NSCLC

Language: Английский

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TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

Nature Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Blockade of immune checkpoints PD-1 and TIGIT has demonstrated activity in mouse tumor models human patients with cancer. Although these coinhibitory receptors can restrict signaling CD8+ T cells by regulating their associated co-stimulatory CD28 CD226, the functional consequences combining blockade remain poorly characterized. In models, we show that combination elicited CD226-driven clonal expansion antigen-specific cells. The expanded clones emerged from a population stem-like draining lymph nodes, entering blood as previously unidentified single-phenotype, multiclonal population. Upon reaching tumor, transiting further differentiated into effector or exhausted cells, restricting entry exhaustion pathway favoring co-stimulation. Thus, inhibition helps shape repertoire tumor-reactive nodes determines immunological fate to enhance therapeutic benefit. Analysis clinical trial samples suggests similar mechanism may also occur Mellman colleagues present multiomic single-cell analysis effects combined anti-TIGIT anti-PD-1 on cell populations trafficking node tumor.

Language: Английский

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Infiltrating T lymphocytes and tumor microenvironment within cholangiocarcinoma: immune heterogeneity, intercellular communication, immune checkpoints

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 8, 2025

Cholangiocarcinoma is the second most common primary liver cancer, and its global incidence has increased in recent years. Radical surgical resection systemic chemotherapy have traditionally been standard treatment options. However, complexity of cholangiocarcinoma subtypes often presents a challenge for early diagnosis. Additionally, high recurrence rates following radical resistance to late-stage limit benefits patients. Immunotherapy emerged as an effective strategy treating various types shown efficacy when combined with cholangiocarcinoma. Current immunotherapies targeting predominantly focused on T lymphocytes within tumor microenvironment, new yielded unsatisfactory results clinical trials. Therefore, it essential achieve comprehensive understanding unique microenvironment pivotal role it. In this review, we describe heterogeneous immune landscape intercellular communication summarize specific distribution lymphocytes. Finally, review potential checkpoints

Language: Английский

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Insights into the future of first-line advanced hepatocellular carcinoma treatment

The Lancet Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Immunomodulation of Pancreatic Cancer via Inhibition of SUMOylation and CD155/TIGIT Pathway

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of E1 enzyme, which catalyzes small ubiquitin-like modifiers (SUMO), with molecule TAK-981, can reprogram TME to enhance immune activation suppress growth. We found CD-155/TIGIT pathway, key regulator evasion in PDAC, influenced by SUMOylation. hypothesized combination SUMO TIGIT would synergistically induce anti-tumor effects. used clinically relevant orthotopic mouse model consistently develops liver metastases study this therapy alone perioperative setting surgical resection. The significantly prolonged survival. Complete responders exhibited protective immunity enhanced T cell reactivity model-specific alloantigens. Complementary analyses resected tumors demonstrated more reduces abundance regulatory FOXP3+CD4+ cells than each monotherapy alone. findings suggest enhances antibody-mediated elimination Tregs through innate cells, potentially type I interferon responses. Our results highlight mechanism efficacy anti-TIGIT therapy. Brief Summary SUMOylation post-translational modification process critical for cancer. Inhibition improve sensitivity pancreatic checkpoint inhibition.

Language: Английский

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Fc-competent TIGITx4-1BB bispecific antibody exerts potent long-lasting antitumor activity by potentiating CD8⁺T cell activity and Fcγ receptor-mediated modulation of the tumor microenvironment

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010728 - e010728

Published: Feb. 1, 2025

Background TIGIT was identified as a target immune checkpoint for overcoming resistance to PD-(L)1-blocking antibodies. However, the clinical efficacies of antibodies were moderate in monotherapy and mixed combination with PD-(L)1 4-1BB, strong inducible costimulatory receptor, is another attractive antitumor therapeutics. This study investigated whether ABL112, an Fc-competent bispecific antibody targeting 4-1BB (TIGITx4-1BB), would enhance activity via Fcγ receptor (FcγR)-mediated macrophage activation antibody-dependent cell-mediated functions. Methods TIGIT-dependent TIGIT-blocking assessed using reporter Jurkat T cell lines expressing TIGIT, respectively. In vivo confirmed h4-1BB knock-in mice. The main subsets associated ABL112 depleting specific subtypes or FcγR-blocking effects combined pembrolizumab atezolizumab treatment two mouse models different genetic backgrounds. Statistical analysis performed one-way two-way variance (ANOVA) Dunnett’s multiple-comparison test ANOVA Fisher’s test. Results restored by blocking TIGIT–CD155 interactions, based on blockade assay. TIGITx4-1BB antibody, showed FcγRI-dependent along activation. H22 tumor high levels endogenous CD155, both parent single-domain Ab potent tumor-suppressive activity; however, only exerted long-lasting activity. induced marked decrease Treg numbers, while augmenting absolute number CD8 + cells proportion CD226 cells. expressions CXCL10, CXCL11, IFN-γ, TNF-α increased, indicating myeloid potential modification microenvironment inflammatory phenotype. not outstanding monotherapy, but also synergistic mAb compared TIGIT–PD-(L)1 treatments. Conclusions Through multiple mechanisms action, tumor-killing memory response alone anti-PD-(L)1 therapies, representing promising new cancer strategy.

Language: Английский

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Exploring the role of TIGIT in patients with Small Cell Lung Cancer as a novel predictor of prognosis and immunotherapy response

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(4)

Published: March 4, 2025

T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) is a novel immune checkpoint playing crucial role in immunosuppression evasion. This study aims to elucidate the expression patterns, characteristics, possible mechanisms of TIGIT small cell lung cancer (SCLC). was analyzed across various cancers normal tissues using The Cancer Genome Atlas (TCGA). Transcriptomic data from SCLC patients, sourced Gene Expression Omnibus (GEO) literature, were assess TIGIT-related characteristics. Immunohistochemistry (IHC) used verify post-surgical advanced samples, focusing on prognostic value, treatment response. significantly overexpressed tumors, including (p < 0.05). Higher associated better overall survival (OS) Notably, significant positive correlation observed between immune-related metagenes, such as HCK, interferon, LCK Immune infiltration analysis revealed strong score multiple cohorts. Additionally, correlated positively cells, CD8 T cytotoxic lymphocytes, B cells 0.05), checkpoints like BTLA, ICOS, LAG3 while it had negative TIDE In validation section, patients high showed prolonged disease-free (DFS) OS demonstrated response adjuvant chemotherapy (ACT) immunotherapy. serves biomarker SCLC, its indicating favorable prognosis These effects may be due TIGIT's unique landscape association other checkpoints.

Language: Английский

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