ImmunoTargets and Therapy最新文献

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has greatly changed the paradigm of cancer treatment in the past decade. However, the efficacy of ICIs in solid tumors is still limited. Even in patients with high PD-L1 expression, the response rate is less than 40%. The immunosuppressive tumour microenvironment (TME) represents a major cause of ICI hyporesponsiveness due to its inhibition on effective T-cell trafficking and immunity. Exploring novel immunotargets and developing combination therapeutics represent promising strategies to improve tumor response to immunotherapy. Immunoglobulin-like transcript (ILT) 4 is a classical inhibitory molecule in myeloid cells. Recently, ILT4 expression was discovered in tumour cells and multiple immunocytes in the TME, functionally inducing tumour growth, metastasis, and immune escape. Our group proposed ILT4 as a novel checkpoint molecule for tumour immunotherapy in 2018. In the past 5 years, translational research on ILT4 has made remarkable advances. Here, we update recent findings on ILT4 function in the TME, summarize the translational research on the development of therapeutic ILT4 antibodies, and highlight emerging clinical trial data supporting the role of ILT4 blockade in improving immunotherapy efficacy.

Immune checkpoint inhibitors (ICIs) have led the advancement of cancer immunotherapy, with remarkable efficacy in many cancers. Prior to the advent of ICIs, prostate cancer had one of the first approvals for cancer immunotherapy with sipleucel-T, an anti-cancer vaccine. Despite this early success, ICIs have since failed to improve outcomes for most patients with prostate cancer, generating a narrative that prostate cancer is resistant immunotherapeutic approaches. Novel therapies like CAR T-cells, bispecific antibody therapies, anti-cancer vaccines and cytokine therapies are now generating early evidence for how the prostate cancer tumor immune microenvironment can be manipulated beyond checkpoint inhibition. Most notably, clinical trials with bispecific T-cell engagers (BiTEs) targeting tumor antigens like STEAP-1 and KLK2 have shown clinical promise. Moving beyond ICIs may lead to new approaches to alter the prostate cancer tumor immune microenvironment and improve clinical outcomes.

Hashimoto's thyroiditis is one of the most common autoimmune diseases, characterized by lymphocytic infiltration, thyroid autoantibody production, and progressive thyroid destruction. Natural killer cells, as innate immune effectors, play a dual role in HT pathogenesis through cytotoxicity, death receptor signaling, inflammasome activation, and secretion of proinflammatory cytokines. Recent studies using single-cell RNA sequencing have revealed functional heterogeneity of NK subsets, suggesting stage-specific roles in either amplifying or regulating inflammation. Moreover, peripheral blood from HT patients shows increased expression of activating receptors such as NKG2D and NKp30, positively correlated with thyroid autoantibody titers, while abnormal activation of the NLRP3 inflammasome drives NK cell-mediated IFN-γ release and thyroid follicular cell pyroptosis. These advances highlight NK cells as both contributors to immune imbalance and potential therapeutic targets. A better understanding of NK cell-related mechanisms will provide novel insights into disease monitoring and the development of targeted interventions for HT.

Purpose: There is limited research data on the management of hepatocellular carcinoma (HCC) patients with Child-Pugh class B (CP-B). This study aimed to evaluate the clinical outcomes and radiation-induced hepatic toxicity (RIHT) of combined intensity modulated radiotherapy (IMRT) and programmed cell death protein 1 (PD-1) inhibitors in advanced HCC patients with CP-B.

Patients and methods: This retrospective study screened 232 CP-B advanced HCC patients who had undergone IMRT, and the irradiation scopes were intrahepatic tumor lesions and/or venous tumor thrombosis. The propensity matching method (PSM) was used to reduce selection bias between the radiotherapy (RT) and RT+PD-1 groups. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints included local progression-free survival (LPFS), out-of-field progression-free survival (outPFS), objective response rate (ORR), disease control rate (DCR), and RIHT.

Results: 50 and 39 patients with CP-B advanced HCC were included in the RT+PD-1 and RT groups. After PSM, 39 patients from each group were matched. The median follow-up duration was 15.53 months (95% CI, 13.83-17.22). The median OS and median PFS of RT+PD-1 group were significantly prolonged than RT group (OS:14.27 months [95% CI, 10.53-not estimable] vs 7.57 months [95% CI, 6.57-10.00], HR = 0.284; 95% CI, 0.153-0.526; p < 0.001), (PFS:9.00 months [95% CI, 5.00-not estimable] vs 4.50 months [95% CI, 3.10-6.00], HR = 0.349; 95% CI, 0.188-0.648; p < 0.001). The ORR of RT+PD-1 group was improved than RT group, 43.6% (95% CI, 27.3-59.9) vs 28.2% (95% CI, 13.4-43.0) (p = 0.157). The incidence of RIHT did not differ between the groups except the RT+PD-1 group experienced increased total bilirubin (≥grade 1) more frequently (p = 0.021).

Conclusion: Combined IMRT and PD-1 inhibitors improved clinical outcomes with a comparable incidence of RIHT to radiotherapy alone in advanced HCC patients with CP-B. The individual combined IMRT and PD-1 inhibitors for CP-B could be cautiously applied weighing the survival benefits and the RIHT risks.

Multiple myeloma (MM) is a kind of plasma cell hematologic malignancy. Notable advancements in patient survival have been achieved due to the clinical application of anti-CD38 monoclonal antibody, chimeric antigen receptor T cells (CAR-T) and bispecific T cell engagers (TCEs). However, the immunosuppressive microenvironment of the bone marrow hinders the effectiveness of these novel immunotherapies, consequently restricting their efficacy. Hence, it is imperative to clarify the exact mechanisms to devise strategies aimed at improving the efficacy of immunotherapy. In this review, we provide a systematic overview of recent research concerning the different T cell subtypes in the immune evasion mechanisms of MM. The review emphasizes the imbalance between the immune surveillance and the immune suppression, and highlight recent studies about unconventional T cells, the metabolic control of immune reactions, and novel therapeutic strategies aimed at addressing immune evasion mechanisms that promote the progression of MM.

Purpose: Directing selective complement activation towards tumor cells is an attractive strategy to promote their elimination. We have generated complement-activating multimeric immunotherapeutic complexes (CoMiX), stimulating either the alternative pathway (via Factor H Related protein 4 (FHR4)) or the classical pathway (via triple Fc dimers) on HER2-expressing tumor cells.

Methods: We used the C-terminal α-chain multimerizing scaffold of the C4 binding protein (C4bp) to generate CoMiX-FHR4 as well as CoMiX-Fc with 2 different anti-HER2 V_HH, V_HH(T) and V_HH(P), recognizing trastuzumab- or pertuzumab-competing epitopes, respectively. The different CoMiX were compared in vitro for C3b and C5b9 depositions, complement-dependent cytotoxicity (CDC), and their ability to activate NK cells and phagocytosis by macrophages. We further explored their therapeutic efficacy on human BT474 tumor xenografts established in nude mice.

Results: CoMiX-FHR4/V_HH(T) and -FHR4/V_HH(P) lead to the highest C3b and C5b9 depositions and CDC on BT474 tumor cells (p<0.0001), both individually and in combinations with their CoMiX-Fc counterparts, surpassing the low complement activating capacity of trastuzumab and pertuzumab. All CoMiX induced BT474 cell death and phagocytosis of tumor cells by macrophages while CoMiX-Fc also stimulated NK cell activation. In human BT474 xenografts sensitive to trastuzumab, CoMiX induced a massive C3b deposition 6 hours after injection. CoMiX-FHR4 reduced the tumor volume compared to controls (p< 0.05) but to a lesser extent than trastuzumab (p< 0.001) while CoMiX-V_HH(P)/Fc led to a tumor volume reduction similar to pertuzumab. Combinations of two CoMiX-FHR4 or two CoMiX-Fc were more potent, similarly to the combination of trastuzumab and pertuzumab, leading to increased NK cell infiltration in xenografts. Importantly, CoMiX-FHR4 was still active against trastuzumab-resistant xenografts, delaying tumor growth and inducing a large NK cell infiltration.

Conclusion: We showed here that directed complement activation on tumor cells is an alternative to therapeutic antibodies for future combination therapies upon resistance to standard-of-care treatment.

Immunotherapy has transformed cancer treatment and outcomes, although resistance mechanisms remain challenging, prompting exploration of additional immune targets, including B7-H3/CD276. Indeed, B7-H3/CD276's complex and contrasting functions mark it as a jack of all trades, challenging conventional classifications of immune markers. B7-H3/CD276 is a protein belonging to the B7 family of immune regulatory molecules. It participates in immune response modulation and has been implicated in both immune activation and suppression, depending on the context though its precise immune function remains incompletely defined. B7-H3/CD276 expression is observed in various cancers and inflammatory conditions. In regard to cancer, there appears to be variability in expression both between and within malignancy types. B7-H3/CD276 targeting therapies have shown promising evidence of activity, particularly in patients over-expressing the B7-H3/CD276 protein based on immunohistochemistry. Here, we detail B7-H3/CD276's proposed immunologic and metabolic roles in the pathogenesis and progression of cancer, describe its heterogeneous patterns of RNA expression in a pan-cancer cohort, and summarize early clinical trial outcomes data.

Purpose: This study aimed to evaluate the clinical efficiency and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with hepatocellular carcinoma (HCC) and lung metastasis.

Methods: In this multicenter retrospective study, treatment-naive patients with advanced (BCLC stage C) HCC and lung metastases who received lenvatinib and PD-1 inhibitor - with or without HAIC - between January 2019 and January 2024 were reviewed. Propensity score matching (PSM) was applied to balance baseline characteristics between the two groups. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) according to RECIST 1.1 criteria, as well as adverse events (AEs).

Results: A total of 422 eligible patients were included, with 169 receiving HAIC (HLP group) and 253 receiving lenvatinib plus PD-1 inhibitor (LP group). After 1:1 PSM, 151 patients were matched in each group. The HLP group demonstrated significantly longer median OS compared to the LP group (26.0 versus 8.4 months; hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.27-0.49; P < 0.001). Median PFS was also improved in the HLP group (7.6 versus 5.5 months; HR: 0.77; 95% CI: 0.59-1.00; P = 0.048). ORR and DCR were significantly higher in the HLP group (ORR: 47.7% versus 20.5%, P < 0.001; DCR: 86.1% versus 72.2%, P = 0.003). Although the HLP group experienced a higher incidence of both all-grade and grade 3/4 AEs, all were manageable, and no grade 5 events occurred.

Conclusion: HAIC combined with lenvatinib and PD-1 inhibitor shows promise as a treatment for advanced HCC with lung metastases, offering improved prognosis and a manageable safety profile.

Background: Colorectal cancer (CRC) is a major cause of cancer deaths globally, mainly due to treatment resistance. Neddylation, a key post-translational modification, is linked to tumor growth and immune response, offering potential therapeutic targets, though its role in CRC is not well-explored.

Methods: We examined neddylation-related genes (NRGs) across cell subtypes using CRC scRNA-seq data from the TISCH database. Unsupervised clustering of TCGA and GEO bulk RNA-seq data identified various neddylation patterns. A neddylation-related gene signature (NRGS) was developed using ten machine-learning algorithms and validated externally. The study compared biofunctions, including functional analysis, immune cell infiltration, genomic mutations, enrichment analysis, and responses to immunotherapy and chemotherapy, between high- and low-risk groups defined by the NRGS model.

Results: scRNA-seq analysis showed that the high neddylation score group had more malignant and diverse immune and stromal cells, with activated pathways aiding tumor growth and spread. We identified two neddylation patterns: Cluster A and Cluster B. Cluster B, associated with worse survival, had more immunosuppressive cells and increased tumor progression. We developed a neddylation-related gene signature (NRGS) using ten machine-learning algorithms, which accurately predicted outcomes. Higher risk scores correlated with poorer survival, with AUCs of 0.979, 0.989, and 0.996 for 1-year, 2-year, and 3-year OS in the training cohort. The NRGS was linked to higher recurrence or metastasis, advanced disease stage, and independently predicted OS risk. Patients with high NRGS may resist immunotherapy and standard chemotherapy.

Conclusion: The NRGS could predict outcomes and responses to immunotherapy and chemotherapy in CRC patients, aiding personalized treatment, though further validation is needed.

Background: Splenic immunomodulation triggered by ultrasound shows a significant anti-inflammatory effect against various inflammatory diseases, whose mechanism is mainly attributable to the activation of cholinergic anti-inflammatory pathway (CAP). However, the potential role and underlying mechanism of splenic ultrasound stimulation in cancer management have been rarely reported and superficially defined.

Methods: Following optimization of ultrasonic parameters, this study evaluated the anti-tumor efficacy of splenic sonication across multiple tumor models (eg, orthotopic H22 hepatocellular carcinoma (HCC), orthotopic Hepa1-6 HCC, and subcutaneous 4T1 breast cancer), and applied flow cytometry to quantify dynamic alterations in immune cell populations. Furthermore, in orthotopic H22 HCC models, this study employed fluorescence-activated cell sorting, RNA sequencing, splenic nerve blockade via absolute ethanol ablation, and in vitro Ca²⁺ flux assays to delineate the mechanisms underlying ultrasound-mediated splenic anti-tumor immunity.

Results: This study first assessed the therapeutic effect of focused ultrasound precisely targeting the spleen (FUS sti. spleen) on various tumors at specific ultrasonic doses. It fully demonstrated that FUS directly stimulated splenic immune cell proliferation and activation (especially NK and CD8 T cells) rather than CAP excitation to modulate splenic immune function. Particularly, NK cells are much more indispensable and important in responding to FUS stimulation for cancer suppression than CD8 T cells. RNA sequencing of NK and CD8 T cells, as well as in vitro experiments revealed that FUS firstly regulated calcium-related signaling pathways to further modulate others, such as PI3K-AKT, Rap1, and Hippo pathways to promote immune cell proliferation, migration and activation to suppress cancer cell deterioration. Particularly, FUS sti. spleen and FUS intervention on the tumor synergistically induced the best tumor suppression than each of the two taken individually.

Conclusion: FUS sti. spleen facilitated immunocyte proliferation and activation through altering calcium-dependent signaling rather than CAP excitation to modulate anti-tumor immunity, indicating substantial clinical translation potential.