Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities

British Journal of Cancer, Journal Year: 2023, Volume and Issue: 129(8), P. 1212 - 1224

Published: July 15, 2023

Abstract Immune checkpoint therapies (ICT) can reinvigorate the effector functions of anti-tumour T cells, improving cancer patient outcomes. Anti-tumour cells are initially formed during their first contact (priming) with tumour antigens by antigen-presenting (APCs). Unfortunately, many patients refractory to ICT because tumours considered be ‘cold’ tumours—i.e., they do not allow generation (so-called ‘desert’ tumours) or infiltration existing (T-cell-excluded tumours). Desert disturb antigen processing and priming targeting APCs suppressive factors derived from genetic instabilities. In contrast, T-cell-excluded characterised blocking effective lymphocytes infiltrating masses obstacles, such as fibrosis tumour-cell-induced immunosuppression. This review delves into critical mechanisms which induce T-cell ‘desertification’ ‘exclusion’ in tumours. Filling gaps our knowledge regarding these pro-tumoral will aid researchers developing novel class immunotherapies that aim at restoring more efficient leukocyte trafficking. Such developments expected unleash clinical benefit patients.

Language: Английский

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Cytokine release syndrome and cancer immunotherapies – historical challenges and promising futures

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 25, 2023

Cancer is the leading cause of death worldwide. immunotherapy involves reinvigorating patient's own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific cell engagers, and checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) a serious adverse effect remains major concern. CRS phenomenon hyperactivation that results in excessive cytokine secretion, if left unchecked, it may lead multi-organ failure death. Here we review pathophysiology CRS, its occurrence management context cancer immunotherapy, screening can be used assess de-risk drug discovery earlier clinical setting with more predictive pre-clinical data. Furthermore, also sheds light on potential immunotherapeutic overcome associated activation.

Language: Английский

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Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(1), P. 101377 - 101377

Published: Jan. 1, 2024

Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) response

Language: Английский

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PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy

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

Published: Jan. 3, 2024

Abstract Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells ordinarily show PD-1-dependent exhaustion, it also be efficacious against cancers evading recognition. In such settings, γδ have been implicated, but functional relevance of PD-1 expression by these is unclear. Here we demonstrate intratumoral TRDV1 transcripts (encoding TCRδ chain Vδ1 + cells) predict anti-PD-1 response in patients with melanoma, those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers tissue-derived cells, display transcriptomic program similar to, distinct from, canonical exhaustion colocated CD8 cells. particular, retained effector responses to TCR signaling were inhibitable engagement and derepressed CPI.

Language: Английский

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Targeting conserved TIM3 ⁺ VISTA ⁺ tumor-associated macrophages overcomes resistance to cancer immunotherapy

Science Advances, Journal Year: 2024, Volume and Issue: 10(29)

Published: July 19, 2024

Despite the success of immunotherapy, overcoming immunoresistance in cancer remains challenging. We identified a unique niche tumor-associated macrophages (TAMs), coexpressing T cell immunoglobulin and mucin domain–containing 3 (TIM3) V-domain suppressor activation (VISTA), that dominated human mouse tumors resistant to most currently used immunotherapies. TIM3 + VISTA TAMs were sustained by IL-4–enriching with low (neo)antigenic cell–depleted features. showed an anti-inflammatory protumorigenic phenotype coupled inability sense type I interferon (IFN). This was established cells succumbing immunogenic death (ICD). Dying not only triggered autocrine IFNs but also exposed HMGB1/VISTA engaged TIM3/VISTA on suppress paracrine IFN-responses. Accordingly, blockade synergized paclitaxel, ICD-inducing chemotherapy, repolarize proinflammatory killed via tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) signaling. propose targeting overcome immunoresistant tumors.

Language: Английский

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The current status and future of targeted-immune combination for hepatocellular carcinoma

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 5, 2024

Hepatocellular carcinoma (HCC) is one of the most common cancers and third leading cause death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation radiotherapy, targeted drug therapy with agents such as sorafenib. However, tumor microenvironment liver cancer has a strong immunosuppressive effect. Therefore, new treatments for are still necessary. Immune checkpoint molecules, programmed death-1 (PD-1), death-ligand 1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), along high levels cytokines, induce cell inhibition key mechanisms immune escape in HCC. Recently, immunotherapy based on inhibitors (ICIs) monotherapy or combination tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, topical therapies offered great promise treatment cancer. In this review, we discuss latest advances ICIs combined drugs (targeted-immune combination) other targeted-immune regimens patients advanced HCC (aHCC) unresectable (uHCC), provide an outlook future prospects. The literature reviewed spans last five years includes studies identified using keywords "hepatocellular carcinoma," "immune inhibitors," "targeted therapy," "combination "immunotherapy".

Language: Английский

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Advancing precision cancer immunotherapy drug development, administration, and response prediction with AI-enabled Raman spectroscopy

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

Published: Jan. 9, 2025

Molecular characterization of tumors is essential to identify predictive biomarkers that inform treatment decisions and improve precision immunotherapy development administration. However, challenges such as the heterogeneity patient responses, limited efficacy current biomarkers, predominant reliance on single-omics data, have hindered advances in accurately predicting outcomes. Standard therapy generally applies a "one size fits all" approach, which not only provides ineffective or but also an increased risk off-target toxicities acceleration resistance mechanisms adverse effects. As emerging multi- spatial-omics platforms continues evolve, effective tumor assessment platform providing utility clinical setting should i) enable high-throughput robust screening variety biological matrices, ii) provide in-depth information resolved with single subcellular precision, iii) accessibility economical point-of-care settings. In this perspective, we explore application label-free Raman spectroscopy profiling tool for immunotherapy. We examine how spectroscopy's non-invasive, approach can deepen our understanding intricate inter- intra-cellular interactions within tumor-immune microenvironment. Furthermore, discuss analytical spectroscopy, highlighting its evolution be utilized "Raman-omics" approach. Lastly, highlight translational potential integration practice safe precise patient-centric

Language: Английский

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Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 31, 2025

Language: Английский

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ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: May 22, 2023

Abstract Background Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although studies and trials shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% from ICIs therapy due to tumor heterogeneity complexity immune microenvironment. Several recent explored immunosuppression PD-L1 expression activity by post-translational regulation. Our published articles demonstrate ISG15 inhibits adenocarcinoma progression. Whether enhance efficacy modulating remains unknown. Methods The relationship between lymphocyte infiltration was identified IHC. effects on cells T lymphocytes were assessed using RT-qPCR Western Blot vivo experiments. underlying mechanism modification revealed blot, RT-qPCR, flow cytometry, Co-IP. Finally, we performed validation C57 mice as well tissues. Results promotes CD4 + lymphocytes. In vitro experiments demonstrated induces cell proliferation invalidity responses against tumors. Mechanistically, ubiquitination-like modifying effect increased K48-linked ubiquitin chains thus increasing degradation rate glycosylated targeting proteasomal pathway. negatively correlated NSCLC addition, reduced accumulation also splenic promoted cytotoxic microenvironment, thereby enhancing anti-tumor immunity. Conclusions ubiquitination increases chain modification, PD-L1-targeted proteasome More importantly, enhanced sensitivity immunosuppressive therapy. study shows ISG15, a modifier PD-L1, reduces stability may be potential therapeutic target for cancer immunotherapy.

Language: Английский

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Single-cell dissection of Merkel cell carcinoma heterogeneity unveils transcriptomic plasticity and therapeutic vulnerabilities

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(7), P. 101101 - 101101

Published: July 1, 2023

Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution panel patient tumors, revealing phenotypic plasticity subset treatment-naive MCC. The tumor cells "mesenchymal-like" state endowed with an inflamed phenotype that portends better ICI response. This observation is also validated largest whole dataset available from MCC tumors. In contrast, ICI-resistant tumors predominantly express neuroepithelial markers well-differentiated "immune-cold" landscape. Importantly, subtle shift to reverts copanlisib resistance cells, highlighting potential strategies stratification therapeutics harness plasticity, augment treatment efficacy, avert

Language: Английский

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