Background: There was much evidence suggesting that the serum lactate dehydrogenase (LDH) levels reflect the extent of various pathophysiological processes. However, the current information about dynamic change of LDH in COVID-19 pneumonia has not been well investigated. Methods: Study was performed in 87 cases confirmed by COVID-19 infection. The serum LDH levels were determined at diagnosis and follow-up visits. The evaluation of clinical response to therapy was based on chest CT scan. We selected the value of LDH around the data of chest CT scan (− 1 ~ + 1 day). Results: At diagnosis, significant differences in LDH levels were found between non-severe and severe group (P < 0.05). It was demonstrated that increase or decrease of LDH was indicative of radiographic progress or improvement (P < 0.05). The time to LDH normalization (5.67 ± 0.55, days) was positively correlated with the time to radiographic absorption (5.57 ± 0.65 days, r = 0.53, P < 0.05). Applying the cut-off value of the increase in LDH has good specificity to predict disease progression. Conclusions: Serum LDH was validated for its potential usefulness as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia.

Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical practice, only a fraction of patients can benefit from it with durable responses and subsequent long-term survival. Here, we tested the anti-tumor effect of combining PD-L1 blockade with 4-1BB costimulation in 3LL and 4T1.2 murine tumor models. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice more so than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased the number of intratumoral CD103+CD8+ T cells and altered their distribution. Phenotypically, CD103+CD8+ T cells expressed a higher level of 4-1BB and PD-1 than their CD103− counterparts. Administration of PD-L1 mAb and 4-1BB mAb further increased the cytolytic capacity of CD103+CD8+ T cells. In vivo, CD103−CD8+ T cells could differentiate into CD103+CD8+ progeny cells. In a human setting, more CD8+ T cells differentiated into CD103+CD8+ T cells in the peripheral tumor region of lung cancer tissues than in the central tumor region. Collectively, infiltrated CD103+CD8+ T cells served as a potential effector T cell population. Combining 4-1BB agonism with PD-L1 blockade could increase tumor-infiltrated CD103+CD8+T cells, thereby facilitating tumor regression.

Despite the great impact on long-term survival of some cancer patients, the immune checkpoint blockade (ICB) therapy is limited by its low response rates for most cancers. There is a pressing need for novel combination immunotherapies that overcome the resistance to current ICB therapies. Cytokines play a pivotal role in tumor immunotherapy by helping initiating and driving antitumor immune responses. Here, we demonstrated that, besides conventional CD4+ and CD8+ T cells, IL36 surprisingly increased the number of tumor-infiltrating regulatory T (Treg) cells in vivo and enhanced proliferation of Tregs in vitro. Administration of CTLA-4 monoclonal antibodies (mAbs) strongly enhanced IL36-stimulated antitumor activities through depletion of Tregs. In addition, a cancer gene therapy using the IL36-loaded nanoparticles in combination with CTLA-4 mAbs synergistically reduced lung metastasis of breast tumor cells. We further showed that the combined therapy of CTLA-4 mAbs and IL36 led to an increase in proliferation and IFN-γ production by CD4+ and CD8+ T cells when compared to single therapy with CTLA-4 mAbs or IL36. Collectively, our findings demonstrated a new combination therapy that could improve the clinical response to ICB immunotherapy for cancer.

Background: Immunotherapies targeting the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) have shown great promise for a subset of patients with non-small cell lung cancer (NSCLC). However, safe and robust combination therapies are still needed to bring the benefit to broader patient populations.Methods: we performed in vivo treatment with PD-L1 antibody in Lewis lung carcinoma (LLC)-derived murine NSCLC model. Expression of B and T lymphocyte attenuator (BTLA) was detected during treatment. We evaluated the effects of the combination of anti-BTLA and anti-PD-L1 mAbs on tumor growth and overall survival of mice. In addition, distribution and function of immune cells were analyzed by flow cytometry. The role of BTLA in human and murine CD8⁺ T cells and its impact on reversing exhausted phenotype of PD-1⁺CD8⁺ T cell by PD-L1 blockade were analyzed. Furthermore, we investigated expression and distribution of BTLA on lymphocytes in tumor microenvironment of different specimens from NSCLC patients.Results: There was no significant difference overall survival between anti-PD-L1 therapy and IgG in LLC-bearing mice, and BTLA expression was increased on CD8⁺ T cells after PD-L1 antibody treatment. LLC-bearing mice treated with combination of anti-BTLA and anti-PD-L1 therapy had an improved overall survival than anti-BTLA or anti-PD-L1 alone. Compared to monotherapy with anti-BTLA or anti-PD-L1, mice treated with combination therapy demonstrated increased infiltration of CD8⁺ and CD4⁺ T cells, as well as increased expression of IFN-γ, TNF-α and Ki-67 in CD8⁺ T cells. In addition, CD8⁺ T cells co-expressing BTLA and PD-1 exhibited the most exhausted phenotype to resist PD-L1 blockade therapy. Furthermore, BTLA⁺CD8⁺ T cells were abnormally increased in different specimens from NSCLC patients, and CD8⁺ T cells expressing BTLA in NSCLC microenvironment were correlated with clinical response to anti-PD-1 therapy in NSCLC patients.Conclusion: Our results show that BTLA and PD-1 cooperatively inhibit the activity of CD8⁺ T cells and are associated with resistance to PD-1/PD-L1 pathway blockade in NSCLC patients. Anti-BTLA blockade enhances the antitumor efficacy of anti-PD-L1 therapy. Dual BTLA and PD-1/PD-L1 blockade should be further explored to elicit potent antitumor CD8⁺ T-cell responses in NSCLC patients.

The incidence of invasive pulmonary aspergillosis (IPA) in non-neutropenic patients is increasing. This study aimed to evaluate the clinical outcomes and risk factors for mortality in non-neutropenic IPA patients. We conducted a prospective, multicenter study from August 2020 to February 2024, enrolling 565 patients with suspected IPA. The study cohort comprised 195 IPA (non-neutropenic) cases and 370 non-IPA cases. Peripheral blood and bronchoalveolar lavage fluid (BALF) specimens were collected to measure pentraxin-3 (PTX3) levels. Additionally, demographic data, clinical characteristics, and antifungal therapy of each patient were recorded. We analyzed factors associated with 30- and 90-day mortality. IPA patients exhibited higher mortality rates compared to non-IPA patients, with 30-day rates of 26.15% versus 8.38% ( P < 0.001) and 90-day rates of 34.36% versus 13.24% ( P < 0.001). Higher plasma and BALF PTX3 levels were associated with poor prognosis in IPA patients. ROC curve analysis identified optimal PTX3 thresholds of 4.29 ng/mL in BALF (sensitivity, 67.1%; specificity, 81.4%) and 7.11 ng/mL in plasma (sensitivity, 73.4%; specificity, 82.8%) for predicting mortality. Multivariate Cox regression analysis confirmed PTX3 levels in plasma (hazard ratio [HR] 3.87, 95%CI [1.87–8.00], P ＜0.001) and BALF (HR 2.40 [1.19–4.84], P = 0.014) were independent prognostic factors for IPA mortality. Additionally, positive galactomannan test results in both BALF and plasma were initially correlated with increased mortality in IPA patients. However, after adjusting for potential confounding factors, this correlation no longer remained statistically significant. In conclusion, PTX3 is a promising prognostic biomarker of mortality in IPA patients. IMPORTANCE: Studies have confirmed the value of pentraxin-3 (PTX3) in the diagnosis of invasive pulmonary aspergillosis (IPA), yet its prognostic significance in IPA remains unclear. This study found that in non-neutropenic IPA patients, plasma and bronchoalveolar lavage fluid (BALF) levels of PTX3 are independently associated with poor outcomes. Furthermore, the optimal cutoff values of PTX3 for predicting a poor prognosis of IPA are 4.29 ng/mL in BALF and 7.11 ng/mL in plasma. These findings could help us better manage IPA in non-neutropenic patients, potentially enhancing the prognosis of patients with this condition.