This study aimed to compare the efficacy and safety of atezolizumab plus bevacizumab (T+A) in combination with transarterial chemoembolization (TACE) (T+A+TACE) and T+A for patients with advanced hepatocellular carcinoma (HCC).

From December 2020 to August 2024, 83 patients with advanced HCC who received T+A+TACE treatment or T+A treatment in our hospital were included, and these patients were categorized into TACE+T+A group (n=52) and T+A group (n=31). The clinical outcomes between the two groups were analyzed and compared, and the prognostic factors that affected the efficacy were analyzed.

The median overall survival (OS) and median progression-free survival (PFS) in the T+A+TACE group were significantly longer than those of in the T+A group (OS: 22.8 vs 16.9 months, P = 0.015; PFS: 7.1 vs 4.9 months, P = 0.006). A significantly higher objective response rate (ORR) and disease control rate (DCR) that are based on the modified RECIST were achieved in the T+A+TACE group than those of in the T+A group (ORR: 51.9% vs 6.5%, P < 0.001; DCR: 88.5% vs 54.8%, P < 0.001). No significant differences in adverse events (AEs) were observed between the two groups (P > 0.05). The T+A+TACE treatment was identified as a protective factor for OS and PFS.

TACE further improved the efficacy of T+A treatment for patients with advanced HCC, and it did not increase the incidence of AEs. T+A+TACE treatment is a promising treatment option for patients with advanced HCC.

The addition of a programmed death-ligand 1 (PD-L1) inhibitor, either atezolizumab or durvalumab, to platinum-etoposide prolonged survival in a limited subset of patients with extensive-stage small-cell lung cancer (ES-SCLC). Preclinical studies demonstrated synergistic antitumor activity of combined vascular endothelial growth factor receptor and PD-L1 inhibition in SCLC. Since bevacizumab added to platinum-etoposide was safe and active in ES-SCLC, we investigated the efficacy of atezolizumab, bevacizumab, carboplatin, and etoposide as first-line treatment of ES-SCLC.

The CeLEBrATE study is an Italian multicentric single-arm phase II trial of carboplatin (area under the curve 5 ml/min), etoposide (100 mg/sqm), bevacizumab (7.5 mg/kg), and atezolizumab (1,200 mg) every 3 weeks (q3w) for four to six courses, followed by bevacizumab and atezolizumab maintenance q3w in patients with ES-SCLC and no contraindications to immunotherapy or antiangiogenic therapy. Patients with asymptomatic brain metastases were eligible. Prophylactic cranial irradiation and consolidation thoracic external radiotherapy were not permitted while on study treatment. Primary endpoint was overall survival (OS) rate at 1 year.

53 patients were enrolled (45.3% women, median age 65 years) and received at least one dose of study treatment. At a median follow-up time of 23.4 months (95% CI: 21.1 to 26.0), the 1-year OS rate was 61.8% (90% CI: 50.7% to 72.8%; p=0.04), with a median OS of 12.9 months (95% CI: 11.6 to 17.5). Median progression-free survival was 6.2 months (95% CI: 5.4 to 6.6) and objective response rate was 83.3% (95% CI: 69.8% to 92.5%). Grade 3-4 adverse events were reported in 34 patients (64.2%) leading to dose reductions in 24 (45.3%), and dose delays in 39 (73.9%) and 32 (69.6%) during the induction and maintenance phase, respectively. 19 (35.8%) treatment-related serious adverse events were reported.

The CeLEBrATE study met its primary objective demonstrating a signal of efficacy of bevacizumab, atezolizumab, carboplatin, and etoposide in the first-line treatment of patients with ES-SCLC.

GOIRC-01-2019 ML41241, Eudract Number: 2019-003798-2.

Over the past few years, immune checkpoint inhibitors resulted in magnificent and durable successes in treating cancer; however, only a minority of patients respond favorably to the treatment due to a broad-spectrum of tumor-intrinsic and tumor-extrinsic factors. With the recent insights gained into the mechanisms of resistance, combination treatment strategies to overcome the resistance and enhance the therapeutic potential of immune checkpoint inhibitors are emerging and showing promising results in both pre-clinical and clinical settings. This has been derived through multiple interconnected mechanisms such as enhancing tumor immunogenicity, improving neoantigen processing and presentation in addition to augmenting T cell infiltration and cytotoxic potentials. In the clinical settings, several avenues of combination treatments involving immune checkpoint inhibitors were associated with considerable improvement in the therapeutic outcome in terms of patient's survival and tumor growth control. This, in turn, increased the spectrum of cancer patients benefiting from the unprecedented and durable effects of immune checkpoint inhibitors leading to their adoption as a first-line treatment for certain cancers. Moreover, the significance of precision medicine in cancer immunotherapy and the unmet demand to develop more personalized predictive biomarkers and treatment strategies are also highlighted in this review.

Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration, creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. In this study, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs.

Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies.

The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers.

This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently-available and future potential immunotherapies targeting these pathways were extracted from the searched studies.

The immune checkpoint family consists of many molecules, including CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans.

With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism.

Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.

Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.

Effective first-line treatments for unresectable intrahepatic cholangiocarcinoma (ICC) remain limited. This real-world study aimed to compare the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy combined with or without Lenvatinib as first-line treatment in unresectable ICC patients and identify predictors of treatment response and prognosis.

In this retrospective cohort study, 58 patients with unresectable ICC received either dual therapy (ICIs plus chemotherapy) or triple therapy (ICIs plus chemotherapy and Lenvatinib) as first-line treatment. The endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Survival curve was plotted by the Kaplan-Meier method. A Cox proportional hazards model was performed to investigate risk factors of PFS and OS.

No significant differences were observed between triple therapy and dual therapy as first-line treatment for unresectable ICC patients in terms of PFS (median PFS: 10.3 vs. 11.1 months, P > 0.05) and OS (median OS: 14.0 vs. 15.0 months, P > 0.05). The ORR (39.4% vs. 30.4%) and DCR (90.9% vs. 73.9%) were comparable between the triple therapy group and dual therapy group (P > 0.05). In the multivariate analysis, tumor burden score (TBS, ≥ 8) and tumor number (≥ 2) were associated with prolonged PFS (P < 0.05), while TBS was an independent factor for OS (P < 0.05).

Triple therapy did not demonstrate any benefit on both PFS and OS compared to dual therapy as first-line treatment for patients with unresectable ICC. TBS and tumor number may guide treatment stratification.

Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). Both studies included dose escalation and expansion parts to determine the maximum tolerated dose and recommended phase II dose.

RG6292 was well tolerated. Pruritus and rash were the most frequent adverse events and were manageable with supportive treatment. Serum RG6292 levels increased dose proportionally, independent of the atezolizumab combination. RG6292 induced a sustained dose-dependent depletion of peripheral Tregs with no apparent effect on other immune cells. Evidence of intratumoral Treg reduction (≥50% vs. baseline) was observed at RG6292 doses of 35 to 100 mg. The maximum tolerated dose was 165 mg every 3 weeks, and the recommended phase II dose was proposed as 70 mg every 3 weeks. Objective responses were limited to three partial responses in patients receiving RG6292 combined with atezolizumab.

RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as a single agent or combined with atezolizumab was insufficient to warrant further exploration in this population.

RG6292 (vopikitug) targets CD25 (IL-2Rα) and mediates regulatory T-cell depletion while not interfering with IL-2 signaling. Peripheral and intratumoral Treg depletion was shown in two phase I studies. However, RG6292 alone or in combination with atezolizumab was insufficient to reverse and rescue from established resistance mechanisms in solid tumors.

Immune checkpoint inhibitors (ICIs) have been approved for treating various cancers; however, they can cause immune-related adverse events. Generally, ICIs are not associated with an increased risk of infection, however, several reports demonstrated infections caused by non-tuberculous mycobacterium (NTM) during ICI therapy. Here, we report a case of NTM shoulder arthritis with acute exacerbation immediately after ICI initiation. A 75-year-old man was diagnosed with left shoulder arthritis caused by Mycobacterium intracellulare eight months before receiving ICI treatment and was treated with clarithromycin and ethambutol. However, the mild redness, swelling, heat, and shoulder pain persisted. The patient was diagnosed with hepatocellular carcinoma and atezolizumab and bevacizumab treatment was initiated; one day after the initiation of therapy, the patient presented with a fever and worsened shoulder symptoms. Considering the suspected worsening of NTM arthritis, sitafloxacin was additionally administered, and surgical debridement was performed. M. intracellulare was isolated through culturing shoulder synovial tissue; immunohistochemical staining analysis revealed programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) expression in granulation tissue cells. After the arthritis symptoms decreased, atezolizumab plus bevacizumab was resumed and continued with no recurrence of arthritis. The NTM exacerbation on the day after ICI administration suggests the potential involvement of the PD-1/PD-L1 pathway in the pathogenesis of NTM; moreover, adverse inflammatory reactions to NTM were possibly triggered through the blockade of this pathway.

Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite stable (MSS) phenotype. In our previous study, potassium oxonate (PO), a uricase inhibitor commonly used for elevating uric acid in mice, unexpectedly showed remarkable inhibition of tumor growth when combined with anti-programmed death-1 (PD-1). Further research demonstrated that the combination of potassium oxonate and anti-PD-1 could reprogram the immune microenvironment. This study aimed to explore the anti-tumor effect of PO combined with anti-PD-1, and investigate the impact on the immunosuppressive tumor microenvironment (TME).

We established a syngeneic mouse model of CRC and divided into groups of control group, single drugs group of PO and anti-PD-1, and the combination group. Use the HE staining, immunohistochemistry (IHC) and TUNEL staining of tumor issues to verify the anti-neoplasm of each group. We also tested the changes of TME through flow cytometry of spleen of mice in each group, as well as the IHC of cytokines.

The co-therapy of PO and anti-PD-1 showed admirable anti-tumor effect compared with the control group and the single drug groups. The TME were tended to an environment beneficial for killing tumors by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, and decreasing the amount of regulatory T cells. Moreover, IFN-γ and IL-2 secretion were found to be enriched in the tumor TME.

Our study indicated that combination of PO and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.

Background/Objectives: Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy. Barcelona Clinic Liver Cancer (BCLC) guidelines recommend antiangiogenic agents with immune checkpoint inhibitors as first-line therapy for advanced HCC. We present our experience of treating HCC patients with Atezolizumab-Bevacizumab, their response rates, adverse events, survival, and response and survival predictors. Methods: This retrospective analysis included HCC patients diagnosed at All India Institute of Medical Sciences, New Delhi, India between July 2021 and April 2024 and receiving at least one dose of Atezolizumab-Bevacizumab. The primary outcome was overall response rate (ORR), comprising complete response (CR) and partial response (PR), as per mRECIST criteria. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and predictors of response and survival. Results: Sixty-three patients were analyzed {mean age: 56.0 + 12.7 years; 82.5% males}. Forty-three (68.2%) patients had BCLC stage C HCC. Thirty-five (55.5%) patients belonged to Child-Pugh class A and 28 (44.5%) belonged to Child-Pugh class B. At 1 year, OS was 39% and PFS was 27%. Among 43 patients with data for radiological response, ORR was 48.8% (CR-9.3% and PR-39.5%) and DCR was 62.7% with stable disease (SD) in 13.9% of patients. PD occurred in 37.2% of patients. AFP response predicted radiological response, while Child-Pugh class and BCLC stage predicted survival. Adverse events were reported in 49.2% of patients. Conclusions: Our study shows slightly lower survival than previous studies with Child-Pugh class being the most important determinant of survival. AFP response predicts radiological response and not survival.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in advanced hepatocellular carcinoma and increasingly are being evaluated in earlier stage disease. Herein we explore the role of ICIs pre-liver transplant for liver cancers.

Given the high response rates with combination approaches including locoregional treatments, more patients with liver confined disease, without vascular invasion, who have received ICIs are now being rendered eligible for potential liver transplant. This opportunity to expand the population who may benefit from liver transplant has also come with challenges recognizing the global shortage of organs. Post-liver transplant immunosuppression potentially competes with the immune-stimulating effects of ICIs and graft rejection has been a concern. ICIs may provide an opportunity to maintain patients on the waiting list but an understanding of who is likely to benefit is needed, to circumvent possible toxicities. In addition, ICIs are now considered standard of care, in combination with chemotherapy, for advanced cholangiocarcinoma, where the role of liver transplant is evolving.

As the eligibility criteria globally for liver transplant in the setting of malignancy continues to expand, the integration of ICIs becomes increasingly important.

The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.

The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.

Background/Objectives: Combination therapy with atezolizumab and bevacizumab (ATZ/BEV) is extremely effective and yields a high response rate in patients with hepatocellular carcinoma (HCC). In this study, the efficacy of adding locoregional therapy to ATZ/BEV in patients with stable disease (SD) HCC was investigated. Methods: One hundred five HCC patients who were treated with ATZ/BEV or lenvatinib (LEN) as first-line chemotherapy for unresectable HCC were evaluated on the basis of the modified RECIST criteria. SD patients whose initial antitumor effect was achieved received locoregional therapy, and the overall survival (OS) rate was assessed. Results: This study included 58 ATZ/BEV-treated participants and 47 LEN-treated participants. Twenty-eight SD patients (ATZ/BEV) and 20 SD patients (LEN) were identified. OS was significantly greater in ATZ/BEV-treated patients who also received locoregional therapy than in those who did not receive this additional therapy (p = 0.0343), whereas there was no difference between LEN-treated patients who also received locoregional therapy and those who did not. The locoregional therapy consisted of transcatheter arterial chemoembolization (TACE) and/or radiofrequency ablation (RFA). When assessing the add-on effect of TACE and/or RFA in the SD patients treated with ATZ/BEV, five patients were found to achieve CR. Conclusions: The addition of locoregional therapy, such as TACE/RFA, was found to affect SD patients. When a response is limited during ATZ/BEV therapy, it is important to consider the therapeutic option of adding locoregional therapy, as this additional treatment may contribute to improved prognosis via immune modulation.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle for patients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC.

This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5 mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments.

22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p = .032) and longer PFS (14.0 vs. 6.1 months; p = .022) compared with those with PD-L1 expression < 1%. Grade ≥ 3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased.

This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach.

The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.

We aimed to investigate the prognostic significance of tumor size in metastatic renal cell carcinoma (mRCC) by comparing the effectiveness of dual immune checkpoint inhibitor (IOIO) and immune checkpoint inhibitor combined with tyrosine kinase inhibitor (IOTKI) therapies.

This retrospective observational study included patients with mRCC diagnosed between October 2014 and February 2024 who received IOIO or IOTKI treatment at Kobe University Hospital and 5 affiliated hospitals. Clinical and imaging data were collected, and target lesions were measured according to RECIST v.1.1 criteria. Time-dependent ROC curve analysis was performed to evaluate the prognostic value of tumor size, nephrectomy status, and IMDC risk criteria for progression-free survival (PFS) and overall survival (OS).

The study included 180 mRCC patients, consisting of 99 receiving IOIO therapy and 81 receiving IOTKI therapy. Time-dependent AUC analysis showed that tumor size had a higher predictive ability for PFS and OS in the IOIO group than the IOTKI group. In multivariate analysis, tumor size was a significant independent prognostic factor for PFS (HR: 1.010, 95% CI: 1.004-1.016, P < 0.001) in the IOIO group. Moreover, the AUC for tumor size was consistently superior in predicting outcomes compared to nephrectomy status and IMDC risk classification in the IOIO group. Kaplan-Meier curves indicated that tumor size effectively stratified PFS in both nephrectomized and non-nephrectomized cases.

Tumor size significantly impacts the prognosis of mRCC patients treated with IOIO therapy, demonstrating greater predictive ability than nephrectomy status and IMDC risk classification. These findings suggest that tumor volume should be considered a critical factor in treatment decision-making for renal cancer, particularly in patients undergoing IOIO therapy.

Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.

The vascular endothelial growth factor (VEGF) family includes key mediators of vasculogenesis and angiogenesis. VEGFs are secreted by various cells of epithelial and mesenchymal origin and by some immune cells in response to physiological and pathological stimuli. In addition, immune cells express VEGF receptors and/or co-receptors and can respond to VEGFs in an autocrine or paracrine manner. This immunological role of VEGFs has opened the possibility of using the VEGF inhibitors already developed to inhibit tumor angiogenesis also in combination approaches with different immunotherapies to enhance the action of effector T lymphocytes against tumor cells. This review pursues to examine the current understanding of the interplay between VEGFs and the immune system, while identifying key areas that require further evaluation.

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.

To present the real-world status and explore the predictors of the efficacy and prognosis of first-line treatment for unresectable hepatocellular carcinoma (uHCC).

Real-world data of uHCC patients who underwent first-line treatment at 4 hospitals in Northern Anhui, China, from July 2019 to December 2022 were retrospectively collected. The clinicopathological features, haematological indicators, including superoxide dismutase (SOD) and vascular endothelial growth factor-A (VEGF-A), efficacy and safety data were analysed.

A total of 153 patients were enrolled and most of them treated with targeted therapy combined with immunotherapy (TI). Compared to patients treated with TI, patients who were administrated with TI plus locoregional therapy (TIL) showed longer median progression-free survival (mPFS) and median overall survival (mOS) times (both p < 0.05), with manageable safety profiles. Moreover, compared to patients with low baseline serum levels of SOD, patients with high baseline serum SOD levels had a better treatment efficacy and had longer mPFS and mOS times (all p < 0.05). Subgroup analyses indicated that patients with low SOD levels had longer mPFS times when receiving TIL than when receiving TI (p = 0.005), but, among patients with high SOD levels, their prognoses were not substantially different between TIL and TI (p > 0.05). Additionally, patients in the low-VEGF-A group had a longer mOS time than patients in the high-VEGF-A group (p = 0.004). In comparison with TI, TIL can improve the survival time among patients with high VEGF-A levels but not among patients with low VEGF-A levels.

TI was the most commonly first-line systemic therapy for uHCC patients, with better efficacy and outcomes when combined with locoregional therapy in a certain population. Baseline serum SOD and VEGF-A were found to be potential predictive biomarkers for decision-making, treatment response, and outcome in patients with uHCC in the primary care setting.

CX3CR1 functions as the specific receptor for the chemokine CX3CL1, demonstrating expression across a broad spectrum of immune cells. This underscores its pivotal role in communication and response mechanisms within the immune system. Upon engagement with CX3CL1, CX3CR1 initiates a cascade of downstream signaling pathways that regulate various biological functions. In the context of tumor progression, the intricate and inhibitory nature of the tumor microenvironment presents a significant challenge to current clinical treatment techniques. This review aims to comprehensively explore the tumor-destructive potential shown by CX3CR1+CD8+ T cells. Simultaneously, it investigates the promising prospects of utilizing CX3CR1 in future tumor immunotherapies.

Combining bevacizumab with atezolizumab enhances the antitumor effects of the treatment by activating an immune response. This combination is approved for the treatment of unresectable hepatocellular carcinoma (HCC). An abscopal effect is associated with an immune response triggered by radiation-induced immunogenic cell death, based on experimental models. Thus, combining radiotherapy and immunotherapy is expected to induce an abscopal effect. However, the clinical significance of immunotherapy in the abscopal effect remains unknown due to the rarity of clinical cases. Herein, we report a case of advanced HCC with lung and adrenal metastases. The antitumor efficacy of atezolizumab and bevacizumab (atezo/bev) was enhanced following stereotactic body radiotherapy (SBRT), although atezo/bev did not yield a sufficient therapeutic response pre-SBRT. Furthermore, an abscopal effect following SBRT was not observed during atezolizumab alone but was evoked after resuming bevacizumab in combination with atezolizumab, culminating in the patient achieving a complete response status. These findings suggest that immune activation following radiotherapy may be related to the induction of an abscopal effect in clinical practice as well as in experimental settings, and combining immunotherapy with bevacizumab post-radiotherapy could evoke an abscopal effect in a case of HCC, even though immune checkpoint inhibitor use alone may be insufficient.

Because vascular endothelial growth factor inhibition has been suggested to improve immune cell function in the cancer microenvironment, we examined whether using ramucirumab (RAM) before nivolumab usage is more effective in advanced gastric cancer.

This was a multicenter retrospective observational study. We analyzed patients who received nivolumab monotherapy as the third-line regimen for unresectable advanced or recurrent gastric cancer between October 2017 and December 2022. They were divided into the RAM (RAM-treated) group and the non-RAM (non-treated) group according to the RAM usage in the second-line regimen. The primary outcome was to compare the overall survival after nivolumab administration in the third-line regimen between the RAM and non-RAM groups.

Fifty-two patients were included in the present study: 42 patients in the RAM group and ten patients in the non-RAM group. The median overall survival was significantly longer in the RAM group than in the non-RAM group (8.5 months vs 6.9 months, p < 0.05). In the RAM group, patients without peritoneal metastasis had significantly better median overall survival than those with peritoneal metastasis (23.8 months vs 7.7 months, p = 0.0033). Multivariate Cox-proportional hazards analyses showed that the presence of peritoneal metastasis (hazard ratio, 2.4; 95% confidence interval 1.0-5.7) alone was significantly associated with overall survival in the RAM group.

The use of RAM prior to nivolumab monotherapy may contribute to prolonged survival in patients with gastric cancer, especially those without peritoneal metastasis.

This review assesses the efficacy and safety of the combination of transarterial chemoembolization (TACE) and camrelizumab for treating advanced hepatocellular carcinoma (HCC) and is to provide a goal, evidence-based medical foundation for effectively guiding clinical practice.

We conducted a computerized search of six electronic databases to identify studies pertinent to the combination of TACE and camrelizumab for treating advanced HCC. For further analysis of clinical indicators and adverse events data, we utilized random or fixed-effect models to account for heterogeneity between studies.

As of May 30, 2023, 12 articles were included for Meta-analysis, encompassing 1123 patients with advanced HCC. The results indicated that the combined objective response rate (ORR) and disease control rate (DCR) were 51.1 % and 86.8 %, respectively. Regarding survival indicators, the combined overall survival (OS) and progression-free survival (PFS) were 24.26 months and 11.84 months, respectively. Among the adverse events observed, the highest incidence rates for TACE combined with camrelizumab were fever (all grade: 46.5 %, ≥grade III: 5.0 %), hypertension (all grade: 32.2 %, ≥grade III: 8.5 %), transaminase elevation (all grade: 34.7 %, ≥grade III: 13.4 %), and nausea and vomiting (all grade: 43.9 %, ≥grade III: 2.5 %).

This study demonstrated the efficacy and safety of combining TACE with camrelizumab in treating patients with advanced HCC, providing valuable evidence for its prospective clinical application. However, due to the limited availability of clinical data, it is essential to design larger-scale and multi-center clinical randomized controlled trials in the future to validate and confirm these findings definitively.

Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC.

We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022.

In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment.

Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments.

Background: Anti-angiogenic inhibitors and immune checkpoint blockade combination therapy offers a novel approach to circumvent the challenges associated with limited responsiveness to checkpoint inhibitors in bladder cancer. However, the effective strategies for inhibiting angiogenesis in bladder cancer need further elucidation. Objective: This work aims to identify key targets for the effective inhibition of angiogenesis in bladder cancer and to explore the potential benefits of combining anti-angiogenic therapies with immune checkpoint blockade strategies in the treatment of this disease. Methods: Cell-cell interaction analysis was performed using bladder cancer single-cell transcriptome datasets downloaded from the Gene Expression Omnibus (GEO) database to determine the regulatory network driving angiogenesis in bladder cancer. The bladder cancer cell line MBT2 was orthotopically transplanted into mice to investigate the impact of pro-angiogenic molecules on angiogenesis and tumor growth, and to evaluate the synergistic therapeutic potential of a combination therapy targeting angiogenesis and Programmed Cell Death Protein 1 (PD-1). Proliferation and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs) were used to explore the regulatory functions of pro-angiogenic molecules in angiogenesis. Results: Placental growth factor (PGF) is a pro-angiogenic factor in bladder cancer, in addition to vascular endothelial growth factor A (VEGFA). Suppression of PGF reduced the tumor size and angiogenesis in bladder cancer. The expression level of vascular endothelial growth factor receptor 1 (VEGFR1) is higher than that of vascular endothelial growth factor receptor2 (VEGFR2) in the endothelial cells of bladder cancer. The pro-angiogenic activity of PGF is dependent on the expression level of VEGFR1 in endothelial cells. The combined inhibition of PGF and VEGFA exerts a synergistic effect on suppressing tumor growth and angiogenesis. The concurrent inhibition of PGF and VEGFA stands out as the only intervention capable of significantly enhancing the infiltration of CD8+ cytotoxic T cells within the bladder cancer microenvironment. In the bladder cancer mouse model, the introduction of an anti- programmed cell death protein 1 (PD-1) therapeutic regimen combined with the targeted inhibition of PGF and VEGFA, led to a significantly elevated survival rate compared to the outcome observed with anti-PD-1 monotherapy. Conclusion: PGF is a pro-angiogenic molecule in bladder cancer that requires significant expression levels of VEGFR1 in endothelial cells. Notably, the concurrent inhibition of PGF and VEGFA amplifies the therapeutic impact of anti-PD-1 treatment in bladder cancer. These findings provide further insights into the role of PGF in angiogenesis regulation and have conceptual implications for combining anti-angiogenic therapy with immune therapy in bladder cancer treatment.

Tumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study aims to assess the effects of Spi-1 proto-oncogene (SPI1)+CD68+ TAMs in GC.

The distribution of SPI1+CD68+ TAMs in GC tissue was estimated by immunohistochemistry, immunofluorescence, and flow cytometry. Single-cell transcriptome analysis and multiplex fluorescence immunohistochemistry were applied to explore the role of SPI1+CD68+ TAMs in an immune contexture. SPI1 overexpression or knockdown cells were constructed to evaluate its role in macrophage polarization and angiogenesis in vitro and in vivo. Chromatin immunoprecipitation was used to verify the mechanism of SPI1 transcriptional function. The effect of combined antiangiogenic and immunotherapy was further validated using mouse peritoneal metastasis models.

Single-cell transcriptome analysis and immunohistochemistry demonstrated that SPI1 was expressed in macrophages, with a higher enrichment in metastatic lesions than in primary tumors. Higher SPI1+CD68+ TAMs infiltration was associated with poor overall survival. Mechanically, SPI1 promoted the M2-type macrophage polarization. SPI1 could bind to the promoter of vascular endothelial growth factor A and facilitate angiogenesis. Moreover, the level of SPI1+CD68+ TAMs infiltration was closely related to the efficacy of immunotherapy, especially when combined with antiangiogenic therapy.

The present study showed that SPI1+CD68+ TAMs are a promising biomarker for predicting prognosis, antiangiogenic drug sensitivity, and combination target of immunotherapy in patients with GC.

In patients with advanced intrahepatic cholangiocarcinoma (ICC), clinical outcomes remain unsatisfactory despite the recommended first-line treatment of gemcitabine with cisplatin and durvalumab (GCD). We recently reported that hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and durvalumab (HLD) exhibited promising antitumor activity and manageable adverse events in patients with unresectable ICC. Here, we aimed to compare HLD with GCD in patients with advanced ICC. This retrospective study included consecutive patients with advanced ICC administered HLD or GCD between January 2020 and March 2024. Safety and patient outcomes, including overall and progression-free survival and objective response rate, were compared between the two groups. The study cohort included 31 and 28 patients in the HLD and GCD groups, respectively. Compared to the GCD group, the HLD group experienced significantly better overall survival (median, 15.8 vs. 9.6 months; P = 0.033), longer progression-free survival (median, 10.3 vs. 4.1 months; P = 0.007), and a higher objective response rate (46.2% vs. 13.1%; P = 0.009). By subgroup analysis, patients with single tumor, intrahepatic tumors >5 cm, or unilobar tumors benefited more from HLD treatment. Additionally, the rates of any grade and grade 3-4 adverse events were not significantly different between the two groups (100% vs. 92.9%, P = 0.221; 32.3% vs. 42.9%, P = 0.401; respectively). In conclusion, HLD treatment was tolerable and associated with better survival benefits compared to the standard first-line GCD treatment in patients with advanced ICC, especially in those with single tumor, intrahepatic tumors >5 cm, and unilobar tumors.

Immune checkpoint blockade (ICB) has been improving the patient outcome in multiple cancer types. However, not all patients respond to ICB. Biomarkers are needed for selecting appropriate patients to receive ICB. CD74 is an important chaperone that regulates antigen presentation for immune response. However, the relationship between CD74 expression and ICB response remains elusive.

The unified normalized pan-cancer dataset was downloaded from the UCSC database. Wilcoxon Rank Sum Rank Tests were used to analyze the expression differences between normal and tumor samples in each tumor type. Then, the prognostic value of CD74 was determined using univariable Cox proportional hazards regression analysis. The STRING database was utilized to construct the protein-protein interaction (PPI) network of CD74 and the signal pathways were analyzed as well. The correlation of CD74 expression with immune cells and immune regulating genes was investigated in the TIMER database. The TIDE framework was utilized to evaluate the relationship between CD74 expression and the response to immunotherapy. Moreover, the localization of CD74 in the tumor immune microenvironment was verified using multiplex immunohistochemistry. Clinically annotated samples from 38 patients with esophageal cancer treated with neoadjuvant chemotherapy combined with ICB were analyzed for CD74 expression using immunohistochemistry.

In this study, we investigated the prognostic and predictive value of CD74 in different types of cancer. Compared with normal tissue, the expression of CD74 was higher in tumor tissue in various cancers. High expression of CD74 was associated with improved patient prognosis in the majority of cancers. CD74 and its interacting proteins were mainly enriched in the immune-related pathways. The expression of CD74 was significantly positively correlated with B cells, CD4 T-cells, CD8 T-cells, neutrophils, macrophages and dendritic cells. TIDE analysis showed that tumors with high CD74 expression may have better responses to immunotherapy and improved patient survival. In patients with esophageal cancer who had received ICB, higher intratumoral CD74 expression was associated with improved response to ICB.

The findings of this study suggest that the high expression of CD74 may be a potential predictive biomarker of response to ICB.

Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4+ T-cell phenotypes between the 'partial response (PR) + stable disease (SD)' and 'progressive disease (PD)' groups, with an overall increase in CD8+ T-cell phenotypes. Patients with higher frequencies of CD8+PD-1+Ki-67+ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4+Foxp3+PD-1+LAG3+ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC.