Journal for Immunotherapy of Cancer最新文献

Background: Immune checkpoint inhibitor (ICI)-based regimens can be associated with prolonged survival and disease control after treatment discontinuation without further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time both on/off treatment and with/without toxicity. Previous analysis of first-line (1L) nivolumab+ipilimumab for advanced renal cell carcinoma (aRCC) in CheckMate 214 showed treatment-free survival (TFS; time between 1L and second-line (2L) therapies) was twice as long versus sunitinib. TFS and survival states for ICI plus vascular endothelial growth factor receptor-tyrosine kinase inhibitor are of interest.

Methods: In CheckMate 9ER, 651 randomized patients with aRCC received 1L nivolumab+cabozantinib or sunitinib. Minimum follow-up was 4 years. We partitioned area under the Kaplan-Meier OS curve into three survival states defined from randomization: time on 1L protocol therapy, TFS, and survival after 2L subsequent systemic therapy initiation. TFS and protocol therapy were subdivided into mean times with/without grade 2+ treatment-related adverse events. Areas under and between Kaplan-Meier curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported.

Results: At 4 years post-randomization, Kaplan-Meier OS estimates were 49.2% versus 40.2% with nivolumab+cabozantinib and sunitinib, respectively; 17.6% versus 4.7% of patients were in TFS; 15.8% versus 8.2% remained on 1L protocol therapy. The 48-month mean time on protocol therapy for nivolumab+cabozantinib versus sunitinib was 22.6 and 14.1 months; 48-month mean TFS was 7.0 and 4.6 months (difference, 2.4 (95% CI 0.8 to 3.9)); 48-month mean survival after 2L therapy initiation was 5.5 and 12.0 months, respectively. The nivolumab+cabozantinib group spent 8.5 (95% CI 6.2 to 10.8) months more mean survival time on 1L protocol therapy, whereas the sunitinib group had 6.5 (95% CI 4.4 to 8.6) months more mean survival time after 2L therapy initiation. Both treatment groups spent at least half of TFS with grade 2+toxicity, resulting in a difference in mean TFS without toxicity of 0.7 (95% CI -0.4 to 1.8) months.

Conclusions: Partitioned survival analysis over 4 years after initiation of 1L therapy for aRCC indicated that longer OS with nivolumab+cabozantinib versus sunitinib involved more time on 1L therapy and in TFS, and less survival time after 2L therapy initiation.

Trial registration number: NCT03141177.

The inducible T-cell co-stimulator (ICOS, CD278) represents an appealing yet complex target within the CD28 immunoglobulin receptor superfamily. Unlike constitutively expressed co-stimulatory molecules, ICOS is minimally present on naïve T cells and is upregulated following T-cell receptor engagement. This inducible expression pattern, and its crosstalk with other co-stimulatory pathways such as OX40, 4-1BB, CD40, and CD28, position ICOS as a promising candidate for immune agonism. The phase I INDUCE-1 study of the ICOS agonist feladilimab (GSK3359609) employed a pharmacodynamically guided design that prioritized biological activity over toxicity thresholds. Although feladilimab demonstrated favorable safety and robust receptor occupancy, clinical responses were limited-echoing similar experiences with vopratelimab (JTX-2011) and other ICOS agonists. These outcomes highlight that effective ICOS modulation depends not only on receptor engagement but also on spatial and temporal regulation of effector versus regulatory T-cell responses. Future ICOS-directed strategies, whether agonistic or antagonistic, monoclonal or bispecific, will require rational combination approaches and biomarker-driven patient selection to fully harness this pathway's therapeutic potential.

Background: Myeloid-derived suppressor cells (MDSCs) have a dominating presence in the postoperative period, mediating the suppression of natural killer (NK) cells and promoting cancer metastases after surgery. However, their phenotype and effects on postoperative cellular immunity remain incompletely understood. This study aims to functionally characterize surgery-induced (sx) MDSCs and identify potential therapeutic strategies to mitigate their immunosuppressive effects.

Methods: We used multicolor flow cytometry to characterize sx-MDSCs from n=55 patients with cancer undergoing surgery at various time points. Furthermore, single-cell RNA sequencing was performed on a cohort of patients. Our functional ex vivo sx-MDSC:NK cell suppression assay was used to investigate the activity of sx-MDSCs and to screen a 147 small molecule library to identify sx-MDSC antagonists. Lastly, we used preclinical murine models of postoperative metastases to evaluate the therapeutic potential of the inhibitors identified.

Results: Sx-MDSCs significantly expanded after surgery and single-cell RNA sequencing identified signatures resembling immunosuppressive monocytes, including an upregulation of PI3K signaling. These sx-MDSCs also suppressed NK cell activity from patient samples and the small molecule screen identified PI3K-γ inhibitors as potent modulators of sx-MDSC activity. In our murine models, inhibiting PI3K-γ with specific inhibitors reduced postoperative metastases, further corroborating the role of this pathway in sx-MDSC-mediated immune suppression.

Conclusions: Our findings highlight the critical role of PI3K-γ signaling in postoperative sx-MDSC-mediated immune suppression. Targeting this pathway with PI3K-γ inhibitors represents a promising therapeutic strategy to prevent NK cell suppression and reduce postoperative metastases.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs.

Methods: The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting.

Results: Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC.

Conclusions: This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC.

Background: Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies but faces substantial challenges in solid tumors. One of the main obstacles is the extracellular matrix (ECM), which serves as the physical barrier that hinders T cell infiltration into tumor tissues.

Methods: We engineered CAR-T cells targeting mesothelin or B7H3 to co-express matrix metalloproteinase-3 (MMP3). We evaluated the effects of MMP3 overexpression on CAR-T cell proliferation, activation, cytotoxicity, and tumor infiltration using both in vitro Matrigel-based assays and in vivo xenograft and syngeneic models enriched with cancer-associated fibroblasts (CAFs).

Results: MMP3 overexpression did not impair CAR-T cell proliferation, activation, or cytotoxicity. However, it significantly enhanced their capacity to invade through ECM and improved tumor cell killing in vitro. In CAF-enriched xenograft models, MMP3-engineered CAR-T cells demonstrated superior tumor infiltration, expansion, and antitumor activity. Notably, MMP3 overexpression rescued the function of B7H3 CAR-T cells in the stringent CAF-enriched tumor microenvironment, while conventional CAR-T cells showed limited activity. Importantly, MMP3 overexpression also conferred potent antitumor activity in an immunocompetent mouse model, underscoring its therapeutic benefit in a more physiologically and clinically related setting.

Conclusions: These findings suggest that MMP3 engineering is a simple yet effective strategy to overcome stromal barriers and enhance the efficacy of CAR-T cell therapy in solid tumors.

Purpose: This study was conducted to assess the clinical significance of programmed cell death-ligand 1 (PD-L1)-positive circulating tumor cells (CTCs) as predictive biomarkers for the efficacy of PD-(L)1 inhibitor-based treatment in advanced hepatocellular carcinoma (HCC).

Experimental design: We enrolled 59 patients with unresectable HCC who received immunotherapy-based treatment and analyzed CTCs, PD-L1⁺CTCs and molecules in peripheral blood. An innovative telomerase reverse transcriptase-based method was applied to detect specific CTCs. Kaplan-Meier analysis and Cox regression were used to evaluate clinical outcomes, such as progression-free survival (PFS) and overall survival (OS).

Results: CTCs were detected in 86.4% (51/59) of patients, with a PD-L1-positive rate of 83.7% (41/49). Compared with the "PD-L1⁺CTC Low" group, the "PD-L1⁺CTC High" group had significantly shorter PFS (median PFS: 7.72 vs 16.1 months, p=0.037) and shorter OS (median OS: 13.89 vs 36.97 months, p=0.031). The "PD-L1⁺CTC Fewer & Low" group had the longest survival outcomes (median PFS: 17.03 months, median OS: 36.97 months), whereas the "PD-L1⁺CTC More & High" group had the poorest outcomes (median PFS: 5.3 months, median OS: 10.77 months) (p<0.05). Multivariate analysis revealed that the PD-L1⁺CTC count and ratio were an independent predictor of PFS. Significant correlations were found between PD-L1⁺CTC and several immune-related molecules, such as immune checkpoint molecules (CD28, TIM-3, and CD80) and regulatory factors (BDNF, and BLTA).

Conclusions: PD-L1⁺CTCs are potential indicators correlating with the shorter PFS and OS of immunotherapy-based treatment in patients with advanced HCC. The "PD-L1⁺CTC Low & Fewer" classification was associated with better clinical outcomes and immune-related molecules.

Background: Insufficient infiltration of CD8⁺ T cells in the tumor microenvironment (TME) critically restricts antitumor immunity and cancer immunotherapy efficacy. The purpose of this study was to identify novel tumor cell-intrinsic regulators of T-cell infiltration and to elucidate their mechanisms of action.

Methods: We performed a genome-wide Sleeping Beauty transposon mutagenesis screen in murine breast cancer models. Protein-protein interactions were identified by mass spectrometry and validated by co-immunoprecipitation. Gene and protein expression levels were assessed by reverse transcription and quantitative PCR and western blotting. T-cell infiltration and function were evaluated using flow cytometry, immunohistochemistry (IHC), multiplex IHC, and by analyzing bulk and single-cell RNA sequencing data complemented by bioinformatic analysis. The specific dephosphorylation sites on LGALS1 were confirmed through phosphomimetic mutant experiments. T-cell infiltration was further validated using an in vitro T-cell transendothelial migration assay and in vivo mouse models.

Results: Our screening identified 39 candidate genes, with tumor cell-intrinsic dual-specificity phosphatase 22 (DUSP22) expression correlating with enhanced CD8⁺ T-cell accumulation and suppressed tumor progression. Overexpression of DUSP22 resulted in increased CD8⁺ T-cell infiltration and enhanced T-cell function. Mechanistically, DUSP22 binds to LGALS1 and dephosphorylates it at the Ser8 and Thr58 residues, leading to LGALS1 degradation and subsequent alleviation of LGALS1-mediated immunosuppression. In human breast cancer samples, LGALS1 expression was negatively correlated with both DUSP22 levels and CD8⁺ T-cell infiltration. Therapeutic targeting of the DUSP22-LGALS1 axis significantly enhanced CD8⁺ T-cell infiltration and synergized with anti-programmed cell death protein-1 therapy to boost antitumor responses.

Conclusions: Our findings unveil a novel phosphorylation-dependent DUSP22-LGALS1 axis that reprograms the immunosuppressive TME. This work thus proposes a promising therapeutic strategy to overcome immune checkpoint blockade resistance in breast cancer.

Background: Nanosecond pulsed electric field (nsPEF) ablation has demonstrated limited and transient efficacy in suppressing tumor progression. Oncolytic peptide LTX-315 is known to elicit a strong antitumor immune response and durable immune memory. This study aimed to investigate whether LTX-315 could enhance nsPEF-induced antitumor immunity in liver cancer.

Methods: Both cell assays and mouse models were used to evaluate the therapeutic efficacy of nsPEF, LTX-315, and combination therapy. Flow cytometry and immunofluorescence were performed to assess the tumor immune microenvironment. Co-culture models were established to evaluate the functional modulation of immune cells.

Results: nsPEF upregulated the programmed cell death 1 ligand 1 (PD-L1) expression in liver cancer cells, leading to CD8⁺ T-cell dysfunction. LTX-315 reduced the nsPEF-mediated elevated PD-L1 level and restored the cytotoxicity of CD8+ T cells. Furthermore, LTX-315 acted with nsPEF to induce enhanced immunogenic cell death for the activation of dendritic cells and CD8+ T cells. In addition, LTX-315 improved antigen processing and presentation in nsPEF-treated liver cancer cells. Notably, the combination of nsPEF and LTX-315 achieved durable tumor control and prolonged survival of the tumor-bearing mice, by promoting the migration of dendritic cells to tumor-draining lymph nodes, the infiltration of immune cells within the tumor and potential immune memory to prevent tumor metastasis.

Conclusions: LTX-315 functions as an immune stimulant to improve the antitumor efficacy of nsPEF. The combination of nsPEF and LTX-315 represents a promising interventional immunotherapy strategy for liver cancer.

Key points: LTX-315; Antitumor immune response; nsPEF; Liver cancer.

Background: Tumor-associated macrophages (TAMs) are key drivers of the immunosuppressive tumor microenvironment (TME), thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear.

Methods: Both genetic (Akr1b3 knockout) and pharmacologic (epalrestat) approaches were employed to examine the impact of Aldo-keto reductase family 1 member B1 (AKR1B1) inhibition on TAMs and T-cell function in vitro and in vivo. Mechanistic insights were obtained through RNA sequencing, flow cytometry, immunofluorescence staining, and co-culture assays. To assess therapeutic relevance, 4T1 breast cancer and LLC lung carcinoma mouse models were used to evaluate the effects of epalrestat on tumor growth, immune infiltration, and T-cell responses. Clinical relevance was validated in patient cohorts with triple-negative breast cancer (TNBC) and lung adenocarcinoma (LUAD).

Results: AKR1B1 is highly expressed in TAMs and correlates with CD8⁺ T-cell dysfunction. Targeting AKR1B1 enhances antitumor immunity by reprogramming TAMs. Mechanistically, AKR1B1 modulates macrophage metabolism via the glutathione/reactive oxygen species axis, suppressing nuclear factor κB activation and downregulating C-C motif chemokine ligand 5 (CCL5) production, thereby inducing CD8⁺ T-cell dysfunction and establishing an immunosuppressive TME. Inhibition of AKR1B1, either by gene knockout or selective pharmacologic blockade, reprograms TAMs toward an immunostimulatory phenotype, increases CCL5-CCR5 (C-C motif chemokine receptor 5) signaling, restores CD8⁺T cell effector function, and strengthens antitumor immunity. Clinically, high AKR1B1 expression is associated with poor prognosis and immune suppression in TNBC and LUAD. Notably, targeting AKR1B1 improves responses to ICIs in both breast and lung cancer models.

Conclusions: AKR1B1 as a critical regulator of TAM-mediated immunosuppression and highlight its therapeutic potential to enhance the efficacy of ICIs.