Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185). The clinical significances of NET levels before/after treatment and posttreatment changes were statistically evaluated. As a result, multivariate Cox analysis showed that high NET levels before treatment were statistically significant predictors of unfavorable overall survival (OS; p < 0.001, HR 1.702, 95% CI 1.356-2.137) and progression-free survival (PFS; p < 0.001, HR 1.566, 95% CI 1.323-1.855). The Kaplan-Meier curves showed significant separation between the high- and low-NET groups in OS (p = 0.002) and PFS (p < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS (p < 0.001) and PFS (p < 0.001) by multivariate Cox analysis. Notably, the pretreatment NET levels were significantly correlated with the plasma levels of NET-related inflammatory cytokines, such as IL-6 and IL-8, and with NET-related gene expression and immune-suppressive profile in peripheral blood mononuclear cells. Our findings suggest that NETs released from activated neutrophils might reduce the clinical efficacy of ICIs in patients with NSCLC.

UNASSIGNED: Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting.
UNASSIGNED: In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed.
UNASSIGNED: In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia.
UNASSIGNED: Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

BACKGROUND: Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer.
METHODS: An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b+ MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested.
RESULTS: NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer.
CONCLUSIONS: NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.

Glioma, a common and highly malignant central nervous system tumor, markedly influences patient prognosis via interactions with glioma-associated macrophages. Previous research has revealed the anticancer potential of β-mangostin, a xanthone derivative obtained from the mangosteen fruit. This research investigated the role of β-mangostin on microglia in the glioma microenvironment and evaluated the efficacy of β-mangostin combined with anti-PD-1 antibody (αPD-1) in glioma-bearing mice. The results showed that, β-mangostin attenuated M2 polarization in BV2 cells and promoted M1-related interleukin (IL)-1β and IL-6 secretion, thereby inhibiting glioma invasion. In addition, β-mangostin improved the anti-glioma effects of αPD-1 and increased CD8+T cell and M1-type microglia infiltration. Mechanistically, β-mangostin bound to the stimulator of interferon genes (STING) protein, which is crucial for the anti-tumor innate immune response, and promoted STING phosphorylation in microglia, both in vivo and in vitro. These results provide insights into its mode of action and supporting further investigation into β-mangostin as a therapeutic agent.

Skin toxicity is the most common adverse event of treatment with immune check point inhibitors. Among them, erythema multiforme is a rare occurrence with a frequency of 4%, with most of the cases developing grade 1/2 disease. We experienced high grade erythema multiforme major developing with pembrolizumab treatment for anal canal cancer with extensive skin metastases. Steroid ointment was ineffective, and the skin lesions with blisters expanded to > 45% of the body surface area. The patient was at risk for symptom aggravation, and a pulse therapy with methylprednisolone and increasing the dose of oral prednisolone (1 mg/kg) were started. The skin lesions improved in 1.8 months. Unless urgent and appropriate treatments such as high dose steroid administration were conducted, the skin toxicities could not be controlled. The presence of CD4+ T cells and PD-L1+ keratinocytes in the skin biopsy might be a predictive marker of erythema multiforme major resistant to standard steroid treatment.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13691-024-00676-4.

OBJECTIVE: This study aimed to compare the efficacy and safety of combining first-line chemoimmunotherapy with radiation therapy versus chemoimmunotherapy alone in patients with stage IVB esophageal squamous cell carcinoma (ESCC).
METHODS: We retrospectively examined 409 patients with stage IVB ESCC who received first-line chemotherapy and anti-PD-1 antibody, with or without radiation therapy of ≥40 Gy radiation dose to primary lesion, from 4 academic cancer centers between October 2018 and December 2022. Propensity score matching was conducted to minimize the potential confounding effects.
RESULTS: In the overall cohort of 409 patients, the group that received additional radiation therapy had superior overall survival (OS) (hazard ratio [HR], 0.51; 95% CI, 0.39-0.66; P < .001) and progression-free survival (PFS) (HR, 0.52; 95% CI, 0.40-0.66; P < .001) compared to the group that received chemoimmunotherapy alone. After 1:1 propensity score matching, matching age, tumor location, and metastatic sites, a total of 250 patients were selected for further analysis. The results remained consistent and showed that the addition of radiation therapy significantly improved OS and PFS (median OS, 24.9 vs 14.6 months; P = .003; median PFS, 14.2 vs 10.6 months; P = .002). Multivariate Cox analysis including tumor location, T stage, metastatic sites, and treatment modality, revealed that radiation therapy was an independent prognostic factor for both OS (HR, 0.57; 95% CI, 0.41-0.81) and PFS (HR, 0.63, 95% CI, 0.47-0.86). Subgroup analyses revealed significant OS prolongation in patients with nonregional lymph node metastases only who received radiation therapy (HR, 0.49; 95% CI, 0.34-0.70). No OS survival benefit was observed in those with distant organ metastases (HR, 0.72; 95% CI, 0.46-1.13). Regarding safety, the group receiving additional radiation therapy had higher incidences of grade 3 to 4 lymphopenia (74.4% vs 17.7%, P < .001) and esophagitis (11.2% vs 2.4%, P = .006).
CONCLUSIONS: The addition of radiation therapy to chemoimmunotherapy improved the survival of stage IVB ESCC patients with nonregional lymph node metastasis.

SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT.

UNASSIGNED: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy.
UNASSIGNED: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively.
UNASSIGNED: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs).
UNASSIGNED: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies.
RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the \"FG loop\" of hPD-1, distinct from those of Keytruda® (\"C\'D loop\") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201\'s binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME.
CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

Neural cell adhesion molecule L1 (L1CAM) is a cell-surface glycoprotein involved in cancer occurrence and migration. Up to today, L1CAM-targeted therapy appeared limited efficacy in clinical trials although quite a few attempts by monoclonal antibody (mAb) or chimeric antigen receptor T-cell therapy (CAR-T) have been reported. Therefore, the development of new effective therapies targeting L1CAM is highly desirable. It has been demonstrated that T cell-engaging bispecific antibody (TCE) plays an effective role in cancer immunotherapy by redirecting the cytotoxic activity of CD3+ T cells to tumor cells, resulting in tumor cell death. In this study, we designed and characterized a novel bispecific antibody (CE7-TCE) based on the IgG-(L)-ScFv format, which targets L1CAM and CD3 simultaneously. In vitro, CE7-TCE induced specific killing of L1CAM-positive tumor cells through T cells. In vivo, CE7-TCE inhibited tumor growth in human peripheral blood mononuclear cell/tumor cell co-grafting models. To overcome the adaptive immune resistance (AIR) that impairs the efficacy of TCEs, we conducted a combination therapy of CE7-TCE with Pembrolizumab (anti-PD1 mAb), which enhanced the anti-tumor activity of CE7-TCE. Our results confirmed the feasibility of using L1CAM as a TCE target for the treatment of solid tumors and revealed the therapeutic potential of CE7-TCE combined with immune checkpoint inhibitors.