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Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis–treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy’s transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies.

Background: Several immunotherapy (IT) agents are FDA approved for treatment of melanoma and non-small-cell lung cancer (NSCLC). The addition of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT) to immunotherapy looks promising. A systematic review was conducted to evaluate the possible synergistic effects of immune checkpoints inhibitors (ICIs) and stereotactic radiation therapy in melanoma and NSCLC. Materials and methods: Pubmed databases from January 2010 to December 2020 were reviewed to identify English language studies reporting control of local and abscopal effect of the combination of ICI-SBRT/SRS in metastatic NSCLC and melanoma cancer. The inclusion criteria were followed according to PICO criteria. Results: Thirty-nine articles were included of the 2141 initial results. The reported rates for local control were 16.5–100% and 40–94% in brain and extracerebral metastases, respectively. Distant/abscopal response rates were 1–45% in extracerebral metastases. Abscopal effect could not be evaluated in brain metastases because it was not reported in studies. Treatments were well tolerated with few grade 4 toxicities and no grade 5. Conclusions: The combined treatment of ICI-SBRT/SRS achieves high local control and non-negligible abscopal response in patients with extracerebral metastases, with its benefit in cerebral metastases being more controversial. Clinical trials are needed to better characterize the potential synergism.

Background and aims: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. Methods: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. Results: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48–73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. Conclusion: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment. Graphical abstract

Endometriosis is an oestrogen‐dependent disease, and epithelial‐mesenchymal transition (EMT) is involved in the process of endometriosis. Whether oestrogen could induce EMT in endometriosis remains largely unknown. Here, we reported that up‐regulated expression of EMT markers in ovarian chocolate cyst is accompanied by high expression 17β‐hydroxysteroid dehydrogenase 1 (17β‐HSD1), and exposure of primary human endometrial epithelial cells to oestradiol conditions could promote EMT occurrence and activate both β‐catenin and Snail signalling. Furthermore, we found nuclear β‐catenin and Snail expression was closely linked in ovarian endometriosis, and β‐catenin knockdown abrogated oestrogen‐induced Snail mediated EMT in vitro. This is due to that β‐catenin/ TCF‐3 could bind to Snail promoter and activate its transcription. These results suggested that β‐catenin signalling functions as the Snail activator and plays a critical role in oestradiol‐induced EMT in endometriosis.

[This corrects the article DOI: 10.3389/fimmu.2024.1452195.].

Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.

Rechallenge with immune checkpoint inhibitor (ICI) seemed favorable in several tumors, but clinical experience on esophageal squamous cell carcinoma (ESCC) was scanty. This real-world study aimed to assess the feasibility and safety of anlotinib plus ICI for patients with previously ICI-treated advanced ESCC. We retrospectively identified advanced ESCC patients who received anlotinib plus ICI in the rechallenge setting for evaluation of clinical outcomes and safety. Totally 110 ICI-pretreated patients, of which 89 (80.9%) received prior first- or second-line treatment, were included from September 9, 2019, to November 30, 2022. Most patients (63.6%) discontinued initial ICI due to disease progression. After rechallenge, median overall survival (OS) and progression-free survival (PFS) were 11.1 (95% CI, 8.6-13.7) and 5.6 (95% CI, 4.4-6.8) months, respectively; estimated OS and PFS rates at 12 months were 47.6% (95% CI, 36.8%-57.7%) and 21.4% (95% CI, 10.9%-34.2%), respectively. No complete response was reported and 21 (19.1%) patients attained partial response; the objective response rate was 19.1%. Fifty-five (50.0%) had stable disease for a disease control rate of 69.1%. Of the 21 responders, median duration of response was 6.4 months. Tendencies for longer OS were observed in patients with Eastern Cooperative Oncology Group Performance of 0 (P = .056). The incidence of grade 3 or higher treatment-related adverse events was 10.0%. Anlotinib plus ICI in the rechallenge setting was promising and resulted in encouraging benefits for patients with previously ICI-treated advanced ESCC. Our findings provided preliminary but unique evidence to help select ESCC patients benefiting from this strategy. chictr.org.cn; number ChiCTR2300070777.

Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.

Background Immune checkpoint inhibitors (ICIs) can induce severe immune-related adverse events (irAEs) that are life-threatening and may be refractory to standard immunosuppressive therapy. Rituximab has emerged as a potential treatment option, but evidence is limited. Methods We conducted a retrospective multicenter study including patients who received rituximab for severe ICI-related irAEs between 2018 and 2023. Clinical characteristics, type and severity of irAEs, previous immunosuppressive regimens, outcomes after rituximab, and oncologic status were collected. Overall survival was estimated from rituximab initiation. Results Eighteen patients were identified (median age 66 years, 55% male). irAEs were mainly neurological syndromes ( n  = 7), myositis and myocarditis ( n  = 6), and interstitial lung disease ( n  = 3). All events were grade 3–4 according to common terminology criteria for adverse events v5.0 and refractory to corticosteroids, often combined with additional immunosuppressants. Rituximab was administered as second- or third-line therapy. Clinical improvement was observed in 83% of patients, including complete resolution in 39%. After a median follow-up from rituximab initiation of 9.7 months (interquartile range [IQR] 5.1–23.9), seven patients (39%) died, but due to irAE only for three patients (17%). Conclusions Rituximab appears to be an effective therapeutic option for selected severe ICI-related irAEs, particularly when conventional immunosuppressive regimens fail. These real-world data highlight the potential role of B-cell-targeted therapy in the management of complex irAEs and support further evaluation in prospective studies.