Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

The correlation between systemic inflammatory markers and efficiency for advanced gastric cancer patients treated with ICIs combined with chemotherapy.

Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow-up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune-inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12-month OS. A total of 95 patients were included in the validation group, and external validation of the SII-based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance.

Immune checkpoint inhibitors (ICIs) have been extensively used in immunological therapy primarily due to their ability to prolong patient survival. Although ICIs have achieved success in cancer treatment, the resistance of ICIs should not be overlooked. Ferroptosis is a newly found cell death mode characterized by the accumulation of reactive oxygen species (ROS), glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, which has been demonstrated to be beneficial to immunotherapy and combining ferroptosis and ICIs to exploit new immunotherapies may reverse ICIs resistance. Exosomes act as mediators in cell-to-cell communication that may regulate ferroptosis to influence immunotherapy through the secretion of biological molecules. Thus, utilizing exosomes to target ferroptosis has opened up exciting possibilities for reversing ICIs resistance. In this review, we summarize the mechanisms of ferroptosis improving ICIs therapy and how exosomes regulate ferroptosis through adjusting iron metabolism, blocking the ROS accumulation, controlling ferroptosis defense systems, and influencing classic signaling pathways and how engineered exosomes target ferroptosis and improve ICIs efficiency.

Tissue-resident memory T cells in immunotherapy and immune-related adverse events by immune checkpoint inhibitor.

Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.

Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure.

Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity.

Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.

Efficacy of immune checkpoint inhibitors differs in various status of carcinoma: a study based on 29 cohorts with 3255 participants.

BACKGROUND: Pre-clinical data have revealed that viral infection, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV), and Human Papilloma virus (HPV), may lead to the development of "hot" or "immune-sensitive" tumors, which may impact the efficacy of immune checkpoint inhibitor (ICIs). Therefore, This study aimed to investigate the impact of viral status on the efficacy of ICIs. METHODS: Electronic databases were searched to identify relevant trials. The primary endpoints were overall survival (OS) and progression-free survival (PFS) measured by hazard ratio (HR). Stratified analyses were accomplished based on viral types, treatment regimens, and patient locations. RESULTS: A total of 3255 participants were recruited, including 252 cases of gastric cancer, 156 cases of nasopharyngeal carcinoma, 1603 cases of hepatocellular carcinoma, and 1244 cases of head and neck squamous cell carcinoma. Pooled results demonstrated a significant association between viral infection and favorable outcomes in patients receiving ICIs, including improved OS [HR = 0.67, 95%CI (0.57-0.79), P < 0.0001], increased ORR [OR = 1.43, 95%CI (1.14-1.80), P = 0.0018], and a trend toward enhanced PFS [HR = 0.75, 95%CI (0.56-1.00), P = 0.05]. In subgroup analyses, patients treated with ICIs who were exposed to HBV/HCV or HPV infection exhibited an evidently superior OS without heterogeneity, compared to those without infection. CONCLUSIONS: This study indicated that the presence of viral infection was evidently associated with improved outcomes in cancer patients undergoing ICIs, particularly in cases of HBV/HCV and HPV infections.

Sex-related differences in serum biomarker levels predict the activity and efficacy of immune checkpoint inhibitors in advanced melanoma and non-small cell lung cancer patients.

BACKGROUND: Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization. METHODS: In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies. RESULTS: Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1ß predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS. CONCLUSIONS: Serum IL-1ß, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.

Deep learning based digital pathology for predicting treatment response to first-line PD-1 blockade in advanced gastric cancer.

BACKGROUND: Advanced unresectable gastric cancer (GC) patients were previously treated with chemotherapy alone as the first-line therapy. However, with the Food and Drug Administration's (FDA) 2022 approval of programmed cell death protein 1 (PD-1) inhibitor combined with chemotherapy as the first-li ne treatment for advanced unresectable GC, patients have significantly benefited. However, the significant costs and potential adverse effects necessitate precise patient selection. In recent years, the advent of deep learning (DL) has revolutionized the medical field, particularly in predicting tumor treatment responses. Our study utilizes DL to analyze pathological images, aiming to predict first-line PD-1 combined chemotherapy response for advanced-stage GC. METHODS: In this multicenter retrospective analysis, Hematoxylin and Eosin (H&E)-stained slides were collected from advanced GC patients across four medical centers. Treatment response was evaluated according to iRECIST 1.1 criteria after a comprehensive first-line PD-1 immunotherapy combined with chemotherapy. Three DL models were employed in an ensemble approach to create the immune checkpoint inhibitors Response Score (ICIsRS) as a novel histopathological biomarker derived from Whole Slide Images (WSIs). RESULTS: Analyzing 148,181 patches from 313 WSIs of 264 advanced GC patients, the ensemble model exhibited superior predictive accuracy, leading to the creation of ICIsNet. The model demonstrated robust performance across four testing datasets, achieving AUC values of 0.92, 0.95, 0.96, and 1 respectively. The boxplot, constructed from the ICIsRS, reveals statistically significant disparities between the well response and poor response (all p-values < = 0.001). CONCLUSION: ICIsRS, a DL-derived biomarker from WSIs, effectively predicts advanced GC patients' responses to PD-1 combined chemotherapy, offering a novel approach for personalized treatment planning and allowing for more individualized and potentially effective treatment strategies based on a patient's unique response situations.

γδ T cells and the PD-1/PD-L1 axis: a love-hate relationship in the tumor microenvironment.

Gamma delta (γδ) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of γδ T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of αß T cells. However, γδ T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on γδ T cells. This understanding can serve as a therapeutic foundation for improving γδ T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.

Pituitary-related immune adverse events induced by programmed death Protein-1 inhibitors differ clinically from hypophysitis.

OBJECTIVE: We aimed to elucidate the clinical features of pituitary immune-related adverse events (irAEs) induced by PD-1 inhibitors in a Chinese cohort and the previous literatures. PATIENTS AND DESIGN AND MEASUREMENTS: We retrospectively analysed the clinical manifestations, laboratory examination findings, imaging features and treatments of 14 patients with pituitary irAEs caused by PD-1 inhibitors in our cohort. In addition, we searched PubMed for all English articles on pituitary irAEs induced by PD-1 inhibitors published from 1950 to 2023. A total of 47 articles were included, and the clinical characteristics of 94 patients with pituitary irAEs induced by PD-1 inhibitors in these literatures were compared to the characteristics of our cohort. RESULTS: Among the 14 patients in our cohort with pituitary irAEs induced by PD-1 inhibitors, 12 patients (85.71%, 12/14) exhibited isolated ACTH deficiency (IAD), 100.0% (14/14) of the central adrenocortical insufficiency, and 2 patients showed more than one hypothalamic-pituitary axis injury (14.29%, 2/14). Pituitary magnetic resonance imaging in all the 14 patients showed no pituitary enlargement. In previous studies we reviewed, 82.98% of the total (78/94) presented with pituitary irAEs as IAD, 100.0% (94/94) of the central adrenocortical insufficiency, and 78.33% of the patients showed no abnormality of the pituitary gland (47/60). The pituitary irAEs caused by PD-1 inhibitors did not involve typical manifestations of hypophysitis, such as pituitary enlargement, headache, visual field defects, and multiple pituitary function impairments in our cohort and the previous literatures. CONCLUSION: In our study, pituitary immune-related adverse reactions induced by PD-1 inhibitors mainly manifested isolated ACTH deficiency rather than hypophysitis.

Acute kidney injury in cancer patients receiving anti-vascular endothelial growth factor monoclonal antibody vs. immune checkpoint inhibitors: a retrospective real-world study.

BACKGROUND: Anti-vascular endothelial growth factor monoclonal antibody (anti-VEGF) or immune checkpoint inhibitors (ICIs) combined with chemotherapy are commonly administered to cancer patients. Although cancer patients receiving anti-VEGF or ICIs have been reported to experience an increased risk of acute kidney injury (AKI), comparative studies on the AKI incidence have not been evaluated. METHODS: Cancer patients receiving anti-VEGF or ICIs were retrospectively selected from the hospital information system of the First Affiliated Hospital of Wenzhou Medical University between Jan, 2020 and Dec, 2022 and were divided into two groups according to the treatment regimen: anti-VEGF group and ICIs group. The baseline characteristics were propensity-score matched. The primary outcome was sustained AKI. A comparison of cumulative incidence of sustained AKI was performed by Kaplan-Meier curves and log-rank test. Risks for outcomes were assessed using Cox proportional regression. RESULTS: A total of 1581 cancer patients receiving anti-VEGF (n = 696) or ICIs (n = 885) were included in the primary analysis. The ICIs group had a higher cumulative incidence of sustained AKI within one year than the anti-VEGF group (26.8% vs. 17.8%, P < 0.001). Among 1392 propensity score matched patients, ICIs therapy (n = 696) was associated with an increased risk of sustained AKI events in the entire population (HR 2.0; 95%CI 1.3 to 2.5; P = 0.001) and especially in those with genitourinary cancer (HR 4.2; 95%CI 1.3 to 13.2; P = 0.015). Baseline serum albumin level (> 35 g/l) was an important risk factor for a lower incidence of sustained AKI in the anti-VEGF group (HR 0.5; 95%CI 0.3 to 0.9; P = 0.027) and the ICIs group (HR 0.3; 95%CI 0.2 to 0.5; P < 0.001). CONCLUSIONS: Among cancer patients in this real-world study, treatment with ICIs increased incidence of sustained AKI in one year. Baseline serum albumin level was an important risk factor for sustained AKI. The risk factors for sustained AKI differed between the anti-VEGF group and the ICIs group. TRIAL REGISTRATION: The study has been registered at ClinicalTrials.gov (NCT06119347) on 11/06/2023.

Neuromyelitis optica associated with the use of Atezolizumab in a patient with advanced lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are a pharmacological group increasingly used in Oncology and Hematology. These treatments can lead to autoimmune complications, with neurological conditions, especially central nervous system (CNS) involvement, being rare. We describe a case of seropositive neuromyelitis optica in a patient with locally advanced lung adenocarcinoma treated with Atezolizumab.

Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

Survival analysis of comprehensive treatment in Chinese patients with metastatic melanoma: A retrospective analysis.

BACKGROUND: Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is limited, mainly due to different pathological subtypes. The patients in western countries are mainly skin melanoma (about 90%), while the acral and mucosal types are dominant in China, accounting for 41.8% and 22.6% respectively. Acral and mucosal melanoma have lower response rates to immunotherapy and chemotherapy. OBJECTIVE: Whether immune checkpoint inhibitors can improve the survival of Chinese patients with malignant melanoma, therefore, we conducted a retrospective analysis. METHODS: We analyzed 53 patients with metastatic melanoma treated in our hospital to evaluate the efficacy and safety of PD-1 mAb in Chinese patients with metastatic melanoma, and performed univariate and multivariate analyses of prognostic factors that may affect overall survival (OS). RESULTS: In a study of 125 patients with advanced malignant melanoma, 53 patients participated, with a median follow-up of 16 months. Among these, 69.8% died, and 30.2% remained on treatment. Median progression-free survival (PFS) was 6 months, and median OS was 19 months. Patients treated with immune checkpoint inhibitors had improved outcomes, with a median PFS of 7 months and a median OS of 24 months. Patients with bone metastasis and aberrant Lactate dehydrogenase (LDH) post-treatment had worse prognoses, while immunotherapy was a protective factor. Subgroup analysis showed the benefits of immunotherapy across various patient characteristics. No unexpected toxicities were observed. CONCLUSION: The study highlights the efficacy of immune checkpoint inhibitors, particularly PD-1 mAb, in improving survival outcomes for Chinese patients with metastatic melanoma.

Impact of immune checkpoint inhibitors (ICIs) therapy on interferon-γ release assay (IGRA) and diagnostic value in non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Tuberculosis (TB), a highly contagious respiratory disease, presents a significant global health threat, with a notable increase in incidence reported by the WHO in 2022. Particularly, the interplay between TB and non-small cell lung cancer (NSCLC) gains attention, especially considering the rising use of immune checkpoint inhibitors (ICIs) in cancer treatment. This interplay may influence TB diagnostics and reactivation, warranting a closer examination. METHODS: A retrospective analysis was conducted on clinical data of NSCLC patients with positive T-SPOT results before undergoing anti-tumor treatment at Zhongshan Hospital (Xiamen), Fudan University, from January 1, 2021 to December 31, 2022. We assessed the incidence of tuberculosis reactivation and treatment outcomes among these patients. Moreover, we compared the differences in tuberculosis activity between the ICIs and non-ICIs treatment groups. Additionally, we observed the changes in T-SPOT spot count before and after immunotherapy, analyzing their association with tuberculosis activity and prognosis. RESULTS: A total of 40 NSCLC patients with positive T-SPOT results before treatment were included in the study, with 26 patients in the ICIs treatment group and 14 patients in the non-ICIs treatment group. The study found no significant differences between the two groups in terms of gender, age, stage, histological type, performance status, driver gene expression, and distant metastasis. With a median follow-up time of 10.0 (6.0-14.5) months, three cases (11.5%) in the ICIs treatment group developed tuberculosis activity, diagnosed at 2, 3, and 12 months after ICIs treatment initiation. Conversely, no tuberculosis activity was observed in the non-ICIs treatment group, and the difference between the two groups was not significant (P = 0.186). Among the 32 patients who received ICIs treatment, spot count dynamics were diverse: four cases (12.5%) showed an increase, 12 cases (37.5%) had no change, and 16 cases (50.0%) had a decrease. During the follow-up, the progression rate (PD) was 50.0%, 75.0%, and 62.5% in the three groups, respectively (P = 0.527). Similarly, the mortality rate was 0%, 25.0%, and 25.0%, respectively (P = 0.106). Interestingly, among the patients with decreased spot counts, three cases (18.75%) were diagnosed with active pulmonary tuberculosis. CONCLUSIONS: For NSCLC patients with a positive T-SPOT response undergoing ICIs treatment, our study observed indications of active tuberculosis. The varied T-SPOT spot count changes post-ICIs treatment suggest a complex interaction, potentially linking T-SPOT spot count reduction to tuberculosis reactivation risk. These preliminary findings underscore the importance of further research to more accurately assess T-SPOT's diagnostic utility in this context.

What factors may affect the effect of ICI-combined therapy in patients with metastatic renal cell carcinoma? A meta-analysis.

OBJECTIVE: The prognostic factors of ICI-including combined therapy in patients with metastatic renal cell carcinoma were analyzed by systematic review. METHOD: We searched Web of Science, Cochrane, PubMed, CNKI, Wanfang and other databases for randomized controlled trials and clinical trials of combination therapy including ICIs in the treatment of metastatic renal cell carcinoma. The search time was from the establishment of the database to September 2023. Data were extracted and evaluated with RevMan 5.4 software. RESULTS: Six studies were included, including 4723 patients. The results showed that ① in terms of progression-free survival, the factors of age < 65 years old, male sex, Canada and Western Europe, nephrectomy, different IMDC class, number of organs with metastases and PD-L1 expression ≥ 1% significantly prolonged PFS in patients with metastatic cancer treated by combination therapy including ICIs; ② in terms of overall survival rate, the factors of age < 65 years old, female sex, nephrectomy, different IMDC class and PD-L1 expression ≥ 1% significantly prolonged the OS of patients with metastatic cancer treated by combination therapy including ICIs. CONCLUSIONS: Age, sex, region, nephrectomy, different IMDC class, number of organs with metastases and PD-L1 expression are independent factors influencing the efficacy of combination therapy including ICIs in the treatment of metastatic renal cell carcinoma. Systematic evaluation of baseline indicators of patients with metastatic renal cell carcinoma to predict clinical benefits can effectively improve the benefit rate of patients.

Correlation between immunotherapy biomarker PD-L1 expression and genetic alteration in patients with non-small cell lung cancer.

Programmed death-ligand 1 (PD-L1) has been widely used in immunotherapy evaluation of patients with non-small cell lung cancer (NSCLC). However, the effect is not particularly ideal, and the association between PD-L1 and genetic alterations requires more exploration. Here, we performed targeted next-generation sequencing and PD-L1 immunohistochemistry (IHC) testing for PD-L1 expression on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) in 1549 patients. Our studies showed that surgical method of resection was positively correlated with IC+, and a low tumor mutation burden (TMB) was negatively correlated with TC+. Furthermore, we found that EGFR was mutually exclusive with both ALK and STK11. In addition, the features between PD-L1 expression status and genomic alterations were characterized. These results suggest that clinical characteristics and molecular phenotypes are associated with PD-L1 expression signatures, which may provide novel insights for improving the efficiency of immune checkpoint inhibitors (ICIs) in immunotherapy.