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ObjectivesIn this study, we aimed to examine parameters of cryoablation, tumor characteristics, and their correlations with distant tumor response and survival of liver metastatic melanoma patients receiving cryoablation and PD-1 blockade (cryo-PD-1) combination treatment.Materials and methodsA retrospective study was conducted among 45 melanoma patients who received combined PD-1 blockade therapy and cryoablation for liver metastasis from 2018 to 2022. Cox regression was utilized to determine the associations between factors and overall survival (OS). Changes in cytokines and immune cell compositions in peripheral blood samples following the combined treatment were investigated, along with their correlations with treatment response.ResultsThe mean cycle of cryo-PD-1 combination treatment was 2.2 (range, 1–6), and the 3-month overall response rate (RECIST 1.1 criteria) was 26.7%. Of the 21 patients who failed previous PD-1 blockade therapy after diagnosis of liver metastasis, 4 (19.0%) achieved response within 3 months since combination treatment. The diameter of ablated lesion  ≤ 30 mm, metastatic organs  ≤ 2, and pre-treatment LDH level  ≤ 300 U/L were independent prognostic factors for favorable OS. Further analysis showed patients with intrahepatic tumor size of 15–45 mm, and ablated lesion size of  ≤ 30 mm had significantly higher 3-month response rate (42.9% vs 12.5%; P = 0.022) and survival time (30.5 vs 14.2 months; P = 0.045) than their counterparts. The average increase in NLR among patients with ablated tumor size of  ≤ 3 cm and  > 3 cm were 3.59 ± 5.01 and 7.21 ± 12.57, respectively. The average increase in serum IL-6 levels among patients with ablated tumor size of  ≤ 3 cm and  > 3 cm were 8.62 ± 7.95 pg/ml and 15.40 ± 11.43 pg/ml, respectively.ConclusionSize selection of intrahepatic lesions for cryoablation is important in order to achieve abscopal effect and long-term survival among patients with liver metastatic melanoma receiving PD-1 blockade therapy.

In recent years, cancer immunotherapy has emerged as an exciting cancer treatment. Immune checkpoint blockade brings new opportunities for more researchers and clinicians. Programmed cell death receptor-1 (PD-1) is a widely studied immune checkpoint, and PD-1 blockade therapy has shown promising results in a variety of tumors, including melanoma, non-small cell lung cancer and renal cell carcinoma, which greatly improves patient overall survival and becomes a promising tool for the eradication of metastatic or inoperable tumors. However, low responsiveness and immune-related adverse effects currently limit its clinical application. Overcoming these difficulties is a major challenge to improve PD-1 blockade therapies. Nanomaterials have unique properties that enable targeted drug delivery, combination therapy through multidrug co-delivery strategies, and controlled drug release through sensitive bonds construction. In recent years, combining nanomaterials with PD-1 blockade therapy to construct novel single-drug-based or combination therapy-based nano-delivery systems has become an effective mean to address the limitations of PD-1 blockade therapy. In this study, the application of nanomaterial carriers in individual delivery of PD-1 inhibitors, combined delivery of PD-1 inhibitors and other immunomodulators, chemotherapeutic drugs, photothermal reagents were reviewed, which provides effective references for designing new PD-1 blockade therapeutic strategies. Graphical Abstract

Background PD-1 blockade therapy has emerged as a valuable treatment option for advanced hepatocellular carcinoma (HCC), but its therapeutic response and overall efficacy vary among patients. This study develops an automated framework for predicting response to PD-1 blockade with enhanced accuracy. Methods A comprehensive two-phase investigation was conducted, comprising a retrospective multicenter cohort ( n  = 793) for model development and a prospective cohort ( n  = 60) for validation. We established an integrated predictive framework combining ultrasound radiomics with clinical indicators. Model performance was evaluated by ROC analyses, focusing on the area under the curve (AUC). Molecular analyses of liver tissues were performed to explore mechanisms underlying treatment response. Results The ultrasound radiomics model achieved AUCs of 0.714 (training) and 0.617 (validation). The ensemble model, integrating both modalities, demonstrated superior predictive capability, with AUCs of 0.743 (training) and 0.641 (validation). The ensemble learning model, integrating both imaging and clinical modalities, exhibited superior predictive capability, attaining an AUC of 0.743 in the training cohort and 0.641 in the validation cohort. The ensemble model demonstrated exceptional clinical utility in predicting pathological necrosis following PD-1 blockade before hepatectomy, achieving an AUC of 0.692. Notably, it exhibited strong clinical utility in predicting pathological necrosis post-therapy, achieving an AUC of 0.692. Subsequent KEGG/GO analyses implicated key genes in necroptosis and programmed cell death pathways. Conclusion The proposed ultrasound-based ensemble model offers a non-invasive, reproducible method to predict PD-1 blockade response in HCC, effectively integrating imaging and clinical data to enhance predictive accuracy and reveal potential molecular mediators of therapeutic efficacy. Summary We developed an advanced automated predictive model that synergistically integrates ultrasound imaging with clinical indicators through ensemble learning methodology. This innovative model employs state-of-the-art deep learning architectures, specifically optimized convolutional neural networks, to accurately predict therapeutic response to PD-1 blockade in patients with unresectable hepatocellular carcinoma. Key results ■ In our retrospective analysis, the ensemble learning model demonstrated exceptional predictive capability for PD-1 blockade therapeutic response in HCC. The integrated framework, combining ultrasound radiomics with clinical indicators, achieved an AUC of 0.743 in internal validation and maintained robust performance with an AUC of 0.641 in external validation cohorts. ■ In our prospective validation cohort, the ensemble learning model demonstrated remarkable accuracy in predicting pathological necrosis following PD-1 blockade therapy, achieving an AUC of 0.692. This robust performance highlights the importance of multimodal data integration, combining advanced ultrasound imaging features with comprehensive clinical indicators, for optimizing predictive capabilities in HCC management.

The papillary thyroid carcinoma (PTC) microenvironment consists of various cancer and surrounding cells, and the communication between them is mainly performed through ligand–receptor (LR) interactions. Single-cell RNA sequencing (scRNA-seq) has been performed to investigate the role of intercellular communication networks in tumor progression. In addition, scRNA-seq can accurately identify the characteristics of immune cell subsets, which is of great significance for predicting the efficacy of immunotherapy. In this study, the cell–cell communication network was analyzed through LR pairs, and a new PTC molecular phenotype was developed based on LR pairs. Furthermore, a risk model was established to predict patient response to PD-1 blockade immunotherapy. The scRNA-seq dataset was obtained from GSE184362, and the bulk tumor RNA-seq dataset was obtained from The Cancer Genome Atlas. CellPhoneDB was used for cellular communication analysis. LR pair correlations were calculated and used to identify molecular subtypes, and the least absolute shrinkage and selection operator (Lasso) Cox regression was used to develop a risk model based on LR pairs. The IMvigor210 and GSE78220 cohorts were used as external validations for the LR.score to predict responses to PD-L1 blockade therapy. A total of 149 LR pairs with significant expression and prognostic correlation were included, and three PTC molecular subtypes were obtained from those with significant prognostic differences. Then, five LR pairs were selected to construct the risk scoring model, a reliable and independent prognostic factor in the training set, test set, and whole dataset. Furthermore, two external validation sets confirmed the predictive efficacy of the LR.score for response to PD-1 blockade therapy.

Background Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62L low CD4 + T cells (effector T cells; %Teff) and CD4 + CD25 + FOXP3 + T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. Methods The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. Results This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18–24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. Conclusions The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients' response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients' response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).

IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8 T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer.

Programmed cell death protein 1 (PD‐1) /programmed cell death ligand 1 (PD‐L1) blockade is an important therapeutic strategy for melanoma, despite its low clinical response. It is important to identify genes and pathways that may reflect the clinical outcomes of this therapy in patients. We analyzed clinical dataset GSE96619, which contains clinical information from five melanoma patients before and after anti‐PD‐1 therapy (five pairs of data). We identified 704 DEGs using these five pairs of data, and then the number of DEGs was narrowed down to 286 in patients who responded to treatment. Next, we performed KEGG pathway enrichment and constructed a DEG‐associated protein‐protein interaction network. Smooth muscle actin 2 (ACTA2) and tyrosine kinase growth factor receptor (KDR) were identified as the hub genes, which were significantly downregulated in the tumor tissue of the two patients who responded to treatment. To confirm our analysis, we demonstrated similar expression tendency to the clinical data for the two hub genes in a B16F10 subcutaneous xenograft model. This study demonstrates that ACTA2 and KDR are valuable responsive markers for PD‐1/PD‐L1 blockade therapy.

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti–PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA⁻CD4⁺ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4⁺ or CD8⁺ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti–PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67⁺) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1⁺ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1⁻ eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1⁺ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1⁺ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.