Cancer Immunology, Immunotherapy最新文献

The integration of molecular targeted therapeutics with chimeric antigen receptor T (CAR-T) cell therapy represents a novel strategy to amplify the anti-tumor efficacy of immunotherapy. While CD19-targeted CAR-T cells and Janus kinase (JAK) inhibitors have independently shown efficacy against certain B-cell leukemias, such as Philadelphia chromosome-like acute lymphoblastic leukemia, the concurrent use of JAK1/2 inhibitors, such as ruxolitinib, has been implicated in reducing CAR-T cell potency by inhibiting the JAK1-dependent T cell activation pathway. This study explores the combinatorial use of a selective type II JAK2 inhibitor, CHZ868, with CD19 CAR-T cells, revealing a synergistic enhancement of anti-leukemic activity across B-cell tumor models irrespective of JAK2 mutational status. CHZ868-mediated JAK2 inhibition did not induce the exhaustion of CAR-T cells, maintaining efficacy over repeated tumor challenges and significantly extending survival in mouse models engrafted with JAK2 inhibitor-resistant leukemia cells (median survival, CD19 CAR-T + CHZ868 vs. CD19 CAR-T + DMSO: 32 days vs. 26 days, p = 0.0303). Transcriptomic analyses suggest that CHZ868 impedes CAR-T cell differentiation while preserving their proliferative capacity, a crucial factor in maintaining CAR-T cell functionality. Therefore, the selective inhibition of the JAK2 pathway may potentiate CAR-T cell therapy and offer a viable treatment strategy for patients with resistant B-cell leukemias.

Imiquimod (IMQ), a drug from aminoquinoline group, is the toll-like receptor 7 (TLR7) agonist. It acts as an immunostimulant and radio-sensitizing agent. IMQ stimulates both innate and adaptive immune response. Despite studies conducted, there are no unambiguous data showing how IMQ affects the condition of tumor blood vessels. Tumor vasculature plays the main role in tumor progression. Formation of abnormal blood vessels increases area of hypoxia which recruits suppressor cells, blocks tumor infiltration by CD8⁺ T lymphocytes, inhibits efficacy of chemoterapeutic drug and leads to cancer relapse. Normalization is a type of therapy targeted at abnormal tumor blood vessels. Here, we demonstrated that 50 µg of IMQ inhibits the growth of melanoma tumors more efficiently, compared to other tested doses and the control group. Dose escalation did not improve the therapeutic antitumor potential of TLR7 agonist. A dose of 50 µg of IMQ most effectively reduced tumor blood vessel density. Imiquimod normalized tumor vasculature both structurally (by reducing vessel tortuosity and increasing pericyte coverage) and functionally (by improving tumor perfusion) in a dose-dependent manner. Hypoxia regions in tumors of treated mice were significantly reduced after IMQ administration. A dose of 50 µg of IMQ had also the greatest impact on the changes in tumor-infiltrating T lymphocytes levels. TLR7 agonist inhibited angiogenesis in treated mice. Functional vascular normalization by IMQ increases the effectiveness of low dose of doxorubicin. Higher dose of IMQ showed worse effects than lower doses including decreased tumor perfusion, increased tumor hypoxia and immunosuppression. This knowledge may help to optimize the combination of the selected IMQ dose with e.g. chemotherapy or radiotherapy to elicit synergistic effect in cancer treatment. To conclude, we outline IMQ repurposing as a vascular normalizing agent. Our research results may contribute to expanding the therapeutic indications for the use of IMQ in anticancer therapy in the future.

Introduction: Immune check-point inhibitors (ICI) were a major breakthrough in cancer care, but optimal patient selection remains elusive in most tumors.

Methods: Overall 173 adult patients with metastatic solid tumors candidates to ICI in clinical trials at our Institution were prospectively recruited. Blood samples were collected at cycle 1 (C1D1) and 2 (C2D1) and until the occurrence of progressive disease (PD). C1D1 LIPI, RMH, PMHI, NLR, dNLR, PIPO and GRIm prognostic scores were calculated. The primary endpoint was identifying the best score to predict rapid PD (≤ 4 months) with ICI using logistic regressions accounting for tumor type, and receiving operators characteristics (ROC) with area under curve (AUC), accompanied by an extensive comparison of the score performances in the prediction of overall survival (OS), progression-free survival (PFS), overall response rates (ORR) and durable clinical benefit (DCB). Secondary objectives included describing study cohort outcomes and studying the association between the selected score at C1D1, C2D1 and its dynamics with OS and PFS.

Results: C1D1 LIPI was the best predictor of rapid PD, OS and PFS, regardless of cancer type, compared to other scores. No score was associated to ORR and only RMH to DCB. Baseline LIPI detected three categories of patients with significantly different OS (p < 0.001) and PFS (p = 0.013). The same was observed at C2D1 for OS and PFS (both p = 0.020). Significant LIPI class shifts were observed in the overall population (p < 0.001), rapid progressors (p = 0.029) and non-rapid progressors (p = 0.009). Retaining a good LIPI or experiencing a shift towards a better prognostic class was associated to improved OS (p = 0.009) and PFS (p = 0.006). C2D1 LIPI, but not C1D1, remained significantly associated to rapid PD in multivariable analysis.

Conclusions: LIPI may improve patient selection for ICI and guide treatment adjustments according to on-treatment dynamics in a pancancer context.

Background: Systemic and locoregional combination therapy has demonstrated promising outcomes for unresectable hepatocellular carcinoma (HCC); However, the best combination option remains unknown. This study compared the efficacy and safety of lenvatinib and tislelizumab versus atezolizumab and bevacizumab in combination with transarterial embolization (TAE) plus hepatic artery infusion chemotherapy (HAIC) for unresectable HCC with high tumor burden.

Methods: This multicenter retrospective cohort study enrolled treatment-naive patients with unresectable HCC treated with TAE-HAIC plus lenvatinib and tislelizumab (THLP group) or TAE-HAIC plus atezolizumab and bevacizumab (THTA group). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), tumor response, and adverse events (AEs). Propensity score matching (PSM) was performed to reduce bias.

Results: Of the 240 patients enrolled, 153 and 51 patients were assigned to the THLP and THTA groups, respectively after PSM (3:1). The THLP group showed a longer median OS (22 months vs. 18.2 months; P = 0.412), whereas the median PFS was longer in the THTA group (8.1 months vs. 7 months; P = 0.723), with statistically insignificant intergroup differences. No statistical differences were observed in objective response rate (RECIST 1.1: 33.9 vs. 31.4%; mRECIST: 77.1% vs. 74.5%; P = 0.635), disease control rate (RECIST 1.1: 88.9% vs. 92.2; mRECIST: 92.2% vs. 94.1%; P = 0.716), and in grade 3/4 AEs. Gastrointestinal hemorrhage rate was significantly higher in the THTA group (9.1% vs. 1.6%; P = 0.007). All AEs were controllable and no treatment-related grade 5 AEs occurred.

Conclusions: TAE-HAIC plus lenvatinib and tislelizumab or TAE-HAIC plus atezolizumab and bevacizumab showed similar outcomes for unresectable HCC with high tumor burden, and manageable safety. The results need further validation.

Background: Stereotactic ablative radiotherapy (SABR) is thought to activate T cell responses in patients with cancer, leading to its combination with immunotherapy and chemotherapy for treatment of non-small-cell lung cancer (NSCLC). Here, we aimed to provide a high-resolution transcriptomic profiling of the systemic T cell response following SABR, with or without preceding immunotherapy/chemotherapy.

Methods: We conducted single-cell RNA and T cell receptor (TCR) sequencing of T cells from peripheral blood of seven patients with early-stage NSCLC taken pre- and post-SABR without or with prior immunotherapy and chemotherapy (icSABR). Other flow cytometry, single-cell RNA-seq data and bulk RNA-seq data were used to validate the results.

Results: We uncovered distinct T cell response patterns induced by these treatments: while terminal effector CD8⁺ T cells showed increased cytotoxic and inhibitory scores, and upregulated immune-activated pathways post-SABR, the reverse responses occurred post-icSABR. Furthermore, the proportion of large T cell clones increased and single clone decreased post-SABR, while the opposite was seen post-icSABR. Of note, both SABR and icSABR largely changed TCR clonotypes, which were mainly large clones post-SABR but single clone post-icSABR, and predominantly from terminal effector CD8⁺ T cells and T helper cells, respectively.

Conclusions: These findings reveal a complex interplay between SABR and immunotherapy, with potentially valuable implications for treatment strategies involving SABR and immunotherapy to induce systemic T cell responses for tumor eradication in patients with NSCLC.

Objective: Pancreatic ductal adenocarcinoma (PDAC) has an immune-suppressive tumor microenvironment that contributes to resistance to immunotherapy. This study aimed to demonstrate that elevated sterile alpha motif domain-containing protein 3 (SAMD3) expression in effector CD8⁺ T cells was associated with improved survival in PDAC patients.

Design: We investigated the heterogeneity and gene expression profiles of T cells using a single-cell RNA sequencing (sc-RNA-seq) dataset comprised of human PDAC samples. SAMD3 mRNA expression was further evaluated in a tumor-specific OT-I/ovalbumin (OVA) mouse model. SAMD3 levels and their clinical significance were evaluated via immunohistochemistry (IHC) analysis.

Results: SAMD3 was highly expressed in cytotoxic CD8⁺ T cells, with expression significantly downregulated during T cell exhaustion. SAMD3 levels were positively correlated with CD8⁺ T cell function. In PDAC patients, high SAMD3 levels in T cells were associated with improved overall survival (OS), disease-free survival (DFS), and T cell infiltration. A patient exhibiting partial response to combination immunotherapy also showed high SAMD3 levels in T cells.

Conclusion: SAMD3 is a biomarker of T cell function, with elevated expression in T cells predicting improved survival. These findings highlight the potential of precision immunotherapy approaches for treating PDAC.

Purpose: Microsatellite high instability/deficient mismatch repair (MSI-H/dMMR) colorectal cancer (CRC) has an active tumor microenvironment, rendering it more sensitive to immune checkpoint inhibitors. Given that studies involving patients with MSI-H colorectal cancer with RAS mutations are scarce, we explored the effect of RAS mutations on the TME in patients with MSI-H/dMMR cancer and identified potential prognostic factors.

Methods: Seventy-five patients diagnosed with MSI-H/dMMR colorectal cancer were retrospectively enrolled and divided into RAS-mutant and -wild-type groups. The expression levels of CD11c⁺ dendritic cells, CD4⁺ T cells, CD8⁺ T cells, and regulatory T cell (Treg) markers were detected, and prognostic factors were analyzed.

Results: RAS-mutant MSI-H colorectal patients were more likely to have: (1) higher platelet values; (2) shorter disease-free survival (DFS); (3) lower infiltrated numbers of CD11c⁺ dendritic cells, CD4⁺ T lymphocytes, and CD8⁺ T lymphocytes, and higher infiltrated numbers of Foxp3⁺ Treg cells. In MSI-H/dMMR CRC patients: (1) the high CD11c + , CD4 +,  and CD8 +  cells infiltration group had longer DFS than the low-infiltration group, and Foxp3 + cells infiltration was not significantly correlated with DFS; (2) the RAS mutation status, number of CD11c⁺ cells infiltrated, and carbohydrate antigen 19-9 (CA19-9) level were the potential prognostic factors.

Conclusion: RAS mutations in patients with MSI-H/dMMR CRC may reduce the infiltration of CD11c⁺ dendritic cells, CD4⁺ T cells, and CD8⁺ T cells, and increase the infiltration of Foxp3⁺ Treg cells to affect the tumor microenvironment of patients. RAS gene status, CD11c + cells infiltration, and CA19-9 level were potential prognostic factors for MSI-H/dMMR CRC.

The amazing diversity of B cells within the tumor microenvironment is the basis for the diverse development of B cell-based immunotherapies. Here, we focus on elucidating the mechanisms of tumor intervention mediated by four tumor-infiltrating B lymphocytes. Naive B cells present the initial antigen, germinal center B cell subsets enhance antibody affinity, and immunoglobulin subtypes exert multiple immune effects, while regulatory B cells establish immune tolerance. Together they reflect the complexity of the changing dynamics of cancer immunity. Additionally, we have investigated the dynamic effects of tumor-infiltrating B lymphocytes in immunotherapy and their relationship to prognosis, providing new insights into potential treatment strategies for patients.

Background: Combining the programmed death-1 inhibitor toripalimab and the angio-immuno kinase inhibitor surufatinib showed preliminary antitumor activity in patients with advanced solid tumors in a phase I study. Here, we report the efficacy and safety of this combination regimen in treatment-naive advanced or metastatic non-small-cell lung cancer (NSCLC) patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or greater (PD-L1-positive) and patients with previously treated small-cell lung cancer (SCLC).

Methods: This open-label, single-arm phase II study included patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC or previously treated SCLC in China. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

Results: Forty-three patients were treated (NSCLC cohort, n = 23; SCLC cohort, n = 20). ORRs (95% CIs) were 57.1% (34.0-78.2) in the NSCLC cohort and 15.8% (3.4-39.6) in the SCLC cohort. Median duration of response was not reached (NR) in both cohorts. Median PFS was 9.6 (5.5-NR) and 3.0 months (2.8-4.1), respectively, and median OS was 24.3 (10.8-NR) and 11.0 months (5.0-15.7), respectively. Grade ≥ 3 treatment-related adverse events were reported in 24 patients (55.8%) overall.

Conclusion: Surufatinib plus toripalimab showed encouraging antitumor activity and a tolerable safety profile in patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC and previously treated SCLC.

Myeloid-derived suppressor cells (MDSCs) play a critical role in cancer progression and resistance, thus representing promising targets for immunotherapy. Despite the established role of histone deacetylases (HDACs) in epigenetic regulation of cell fate and function, their specific impact on MDSCs remains elusive. We sought to investigate the effects and underlying mechanisms of HDAC on MDSCs using various HDAC inhibitors. Our results indicate that HDAC1-3 inhibitors reduce CCR2 expression, a chemokine receptor that mediates the migration of monocytic (M-)MDSCs to tumors and attenuated the immunosuppressive activity of MDSCs. In an orthotropic hepatocellular carcinoma (HCC) murine model, HDAC1-3 inhibitors reduced the infiltration of M-MDSCs, increased the number of natural killer cells in tumors, and suppressed tumor growth. Our results also suggest that HDAC1-3 inhibitors potentiate the antitumor effects of anti-programmed cell death protein 1 antibodies. ATAC-seq and RNA-seq analyses revealed 115 genes epigenetically upregulated by HDAC1-3 inhibitors, primarily linked to transcriptional regulation and ubiquitination. We further elucidated that HDAC1-3 inhibitors facilitate CCR2 protein degradation through ubiquitination-mediated by NEDD4 E3 ligase. Our findings reveal a novel mechanism of action of HDAC1-3 inhibitors in MDSCs and suggest a potential synergistic immunotherapy strategy for clinical benefit in HCC.