Immunotherapy advances最新文献

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a transcriptional target gene of the Wnt signalling pathway, is overexpressed in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) and has emerged as a promising therapeutic target. Here, we reflect on the bottom-up development of a novel α-LGR5 therapeutic antibody we have recently reported, into a palette of LGR5-targeting immunotherapeutic modalities: antibody-drug conjugates (ADCs), bispecific T cell engagers (bispecific engagers), and chimeric antigen receptor (CAR) T cells. The α-LGR5 antibody is highly specific and accurately detects LGR5 protein expression levels, enabling its use as a prognostic biomarker for identifying LGR5⁺ tumour types. Preclinical studies road-testing the various α-LGR5-based modalities established potent and safe elimination of LGR5-expressing cancer cells in vitro and efficacy in a mouse model of human cancer in vivo. In this review, we discuss the utility of our antibody as the building block for a novel set of immunotherapeutics and highlight the importance of matching specific α-LGR5-based therapeutic modalities to individual tumour type and patient characteristics.

Monocytes are central to the innate immune system's response to infection or injury. In murine, these cells are classified into distinct subsets: classical monocytes, defined by elevated Ly6C expression (Ly6C^hi), intermediate monocytes (Ly6C^int), and non-classical inflammatory monocytes, characterized by low Ly6C expression (Ly6C^low). Monocytes recruited to tissues differentiate into macrophages, which can be pro-inflammatory or anti-inflammatory, thereby influencing disease processes and outcomes. The principal function of classical monocytes is the mediation of pro-inflammatory reactions, whereas non-classical monocytes are associated with repair and anti-inflammatory processes, patrolling the lumen of the vessels. Growing evidence highlights the importance of monocytes in multiple sclerosis (MS), an autoimmune and neurodegenerative disease of the central nervous system (CNS). Recent studies indicate that modulation of the innate immune system, focusing specifically on the shift from Ly6C^hi to Ly6C^low monocytes, is an effective therapeutic strategy for neurodegenerative diseases, such as Alzheimer's and MS. This transition is crucial for switching the immune response from inflammation to tissue repair and inflammation resolution, emphasizing the plasticity of monocytes and their potential as targets in MS. This review differs from prior studies in that it focuses solely on animal models of MS, which either directly perturb or study monocytes, or where therapeutic approaches mediate their protective effects through monocytes. Such details permit a subtle comprehension of monocyte dynamics in the context of MS.

Therapeutic cancer vaccines are an emerging class of immunotherapy, but challenges remain in effectively adapting approved vaccines to a growing number of adjuvants, combination therapies, and antigen-selection methods. Phase III clinical trials remain the gold standard in determining clinical benefit, but are slow and resource intensive, whilst radiological surrogates often fail to reliably predict clinical benefit. Using immunological surrogates of efficacy, deployed in 'immunobridging trials', could present a viable alternative, safely speeding up cancer vaccine development in a cost-effective manner. Whilst this approach has proven successful in infectious disease vaccines, identifying reliable immunological correlates of protection has proven difficult for cancer vaccines. Most clinical trials, which present the richest source of data to establish a correlate, rely on peripheral blood samples and standard immunoassays that are ill-equipped to capture the complexity of the vaccine-induced anti-tumour response. This review is the first to outline the importance and challenges of establishing immunological surrogates for cancer vaccines in the context of immunobridging trials, evaluating current immunoassay methods, and highlighting the need for techniques that can characterize tumour-infiltrating lymphocytes and the suppressive tumour microenvironment across a range of patients. The authors propose adapting trial designs for surrogate discovery, including combining phase I/II trials and the use of multi-omics approaches. Successful immunological surrogate development could enable future immunobridging trials to accelerate the optimization of approved cancer vaccines without requiring new phase III trials, promoting faster clinical implementation of scientific advances and patient benefits.

Increased knowledge about immune responses to what is perceived as 'foreign' or 'non-self' has revealed extraordinary levels of complexity. Research uncovering these has the potential to optimise immunotherapy. Remarkable progress has been made in transplantation leading to much less acute rejection and a very significant increase in long-term survival. These and other beneficial results have been achieved by stepwise advances, using combinations of less toxic chemotherapies with biological immunosuppressive agents alongside innovatory surgical skills. However, rejection is the default pathway for entities deemed 'foreign', including mistaken suspects like autoantigens. For tumour immunotherapy the identification of bona fide tumour antigens recognised by B and/or T cell receptors has mushroomed but has yet to be optimised to take into account mutations leading to tumour evasion. We are now at the beginning of a road that looks more hopeful by being informed of the complexities. Basic and translational research between the late 1960s and now have yielded an extraordinarily rich harvest of new knowledge. More is to come, further insight is needed and new paradigms explored.

Introduction: Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early stages of CD4⁺ T cell activation remains unclear.

Methods: Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4⁺ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOS^hi T follicular helper cell differentiation.

Results: NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor signals during CD4⁺ T cell re-activation. Phenotypic changes in peripheral blood CD4⁺ T cells in humans on anti-Lag3 and anti-PD-1 combination therapy revealed upregulation of genes encoding ICOS and OX40 on distinct CD4⁺ T cell subsets, highlighting the potential translational relevance of our findings.

Conclusion: Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and may preferentially control NFAT-dependent transcriptional activity during early CD4⁺ T cell re-activation.

Introduction: Behçet's disease (BD) is a chronic, systemic inflammatory condition characterized by recurrent immune dysregulation.

Materials & methods: This study conducted a comprehensive analysis of immune cell subsets, metabolic markers, and their interplay in BD patients. Using multiparametric flow cytometry, we identified elevated Th1 cells, senescent CD8⁺ T cells, and abnormal B cell activation as hallmarks of the chronic inflammatory state in BD.

Results: Despite immunotherapy, innate immune activation persisted, with increased mature NK cells, γδT1 cells, and conventional dendritic cells (cDCs), alongside reduced plasmacytoid dendritic cells (pDCs). Elevated glucose (GLU) and triacylglycerol (TAG) levels in BD patients correlated with increased Th1 cells, functional CD8⁺ T cells, and B cell activation. In vitro experiments demonstrated that GLU and TAG promote Th1 differentiation, CD8⁺ T cell activation, and B cell antibody production, revealing their role as drivers of immune dysregulation.

Conclusion: These findings underscore the intricate relationship between metabolic dysregulation and immune dysfunction in BD, highlighting potential diagnostic and therapeutic targets. Our study provides critical insights into BD pathogenesis, offering a foundation for optimizing disease management and monitoring immune and metabolic markers for improved patient outcomes.

Introduction: The application of neoadjuvant immunotherapy in oesophageal squamous cell carcinoma (ESCC) reactivates anti-tumour immune responses and prolong postoperative survival. However, due to the heterogeneity of tumour microenvironment, limited patients have achieved pathological regression after treatment. The dual roles of B cells were recently highlighted in ESCC. The study aimed to investigate the role of B cell subclusters and the upstream signalling of B cell differentiation in ESCC resistant to immunotherapy.

Methods: Single-cell RNA sequencing was employed for ESCC specimens with distinct responses to neoadjuvant immunotherapy to map the landscape of intra-tumoural B cells.

Results: A novel subset of neuropeptide receptor, receptor activity-modifying protein 1 (RAMP1) positive B cells was revealed to accumulate in ESCC that is resistant to neoadjuvant immunotherapy. Stimulated by nociceptor neurons secreting calcitonin gene-related peptide (CGRP), RAMP1(+) B cells exhibit an immunosuppressive phenotype. The elevated secretion of immune-regulating cytokines by RAMP1(+) B cells blunts the cytotoxicity of Cluster of Differentiation (CD)8(+) T cell and leads to tumour immune evasion. A combination of RAMP1 blocker and anti-Programmed cell death protein (PD)-1 therapies synergistically reinvigorated anti-tumour immunity, reducing tumour progression in vitro.

Conclusion: The study suggests that RAMP1(+) B cells play a critical role in mediating resistance to neoadjuvant immunotherapy in ESCC. Targeting the CGRP-RAMP axis remodels B cells and enhance the efficacy of current immunotherapies, providing new strategies for overcoming treatment resistance.

Introduction: PACIFIC trial demonstrates improved progression-free survival (PFS) and overall survival (OS) in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with platinum-based concurrent chemoradiotherapy (CRT) and adjuvant Durvalumab immunotherapy.

Methods: We retrospectively reviewed 72 consecutive patients with locally advanced NSCLC treated with platinum-based concurrent CRT, who were potentially eligible for adjuvant Durvaluamb treatment (PDL1 ≥1% or inadequate). We analysed PFS, OS, treatment toxicity, and the impact of PDL1 on these outcomes.

Results: The cohort median follow-up was 20 months. Fifty-five patients received adjuvant Durvalumab. The median OS (mOS) has not been reached. OS at 24 months was 67.8% for patients received Durvalumab. The median PFS (mPFS) for patients received Durvalumab was 30 months. PDL1 status (1-49% vs. ≥50%) did not affect outcome in our cohort. Sixteen patients stopped Durvalumab due to immune toxicity. At 24 months, 49% of these patients were still alive versus 76% of the patients who completed 12 months of treatment. The mOS for patients who stopped Durvalumab due to immune toxicity was 16 months, P = .0032. Seventeen patients did not receive adjuvant treatment due to insufficient performance status following CRT and mOS was 6 months.

Conclusions: Our real-world experience demonstrates possibility to achieve similar outcomes to PACIFIC trial. PDL1 status did not affect clinical outcome in our cohort. Patients who stopped adjuvant Durvalumab treatment due to toxicity and those who were not deemed suitable to proceed with adjuvant Durvalumab after CRT, had poorer outcomes. This indicates that careful case selection remains essential.

Introduction: The clinical efficacy of Janus kinase inhibitors (JAKinibs) is highly variable and their safety profiles are poorly understood.

Methods: We established two flow cytometry panels for the assessment of two promising leukocyte biomarkers: signal transducer and activator of transcription (STAT) phosphorylation and cytokine receptor expression. We evaluated the first panel, which assesses phosphorylation levels for STAT1, STAT3, and STAT5 after cytokine stimulation, with or without in vitro pretreatment with JAKinibs, in 10 healthy donors. We then evaluated the second panel, which assesses cytokine receptor expression on T cells and B cells, in five healthy donors.

Results: Stimulation with interleukin (IL)-2 or IL-7 increased STAT5 phosphorylation in T cells but not in B cells or monocytes. IL-6 stimulation induced STAT3 phosphorylation in monocytes and CD4 T cells and, to a lesser extent, in CD8 T cells, but not in B cells. IL-21 stimulation led to STAT3 phosphorylation in T cells and, to a lesser extent, in B cells, but not in monocytes. Interferon-α stimulation increased STAT1 phosphorylation in all cell types. STAT phosphorylation levels were lower after pretreatment with JAKinibs. A dose-response curve was plotted, confirming the correlation between JAKinib concentration and STAT phosphorylation inhibition. The second panel showed that each cell type displayed a distinct pattern of cytokine receptors expression, and that this pattern might be modified by in vitro treatment with JAKinibs.

Conclusion: This preliminary study confirms the utility of flow cytometry for monitoring the biological effects of JAKinibs. Further studies on treated patients are now required to evaluate the clinical value of these two flow cytometry panels.

Tumour-associated macrophages (TAM) are present in the majority of tumours, where they comprise one of the most abundant cell types, influencing tumour progression, metastasis, therapy resistance, and relapse. Hence, there is a great interest in targeting TAMs to improve and complement anti-cancer treatments. However, further studies are needed to validate the potential of exploiting TAM cell surface markers for cancer immunotherapy. Here, we review the function of TAMs, their involvement in tumorigenesis, metastasis, and therapy resistance. Furthermore, we summarize the current landscape of key TAM cell surface receptors that are being investigated as potential targets for cancer immunotherapy, highlighting the promise and challenges associated with these approaches.