Immunosenescence refers to the gradual decline in immune system function with age, increasing susceptibility to infections and cancer in the elderly. The advent of novel immunotherapies has revolutionized the field of cancer treatment. However, the majority of patients exhibit poor re-sponses to immunotherapy, with immunosenescence likely playing a significant role. In recent years, significant progress has been made in understanding the interplay between immunosenescence and immunotherapy. Our research aims to explore the prospects and development trends in the field of immunosenescence and immunotherapy using a bibliometric analysis. Relevant articles were collected from the Web of Science Core Collection (WoSCC) (retrieved on July 20, 2024). Primary bibliometric characteristics were analyzed using the R package "Biblio-metrix," and keyword co-occurrence analysis and visualization were conducted using VOSviewer. A total of 213 English-language original research and review articles spanning 35 years were re-trieved for bibliometric analysis. There was a surge in publications in this field starting in 2017. The United States and China contributed the most articles. Frontiers in Immunology was the most productive journal, while the University of California System was the highest contributing institution. Besse Benjamin from France emerged as the most influential researcher in this field. Popular keywords included "nivolumab," "T cells," "dendritic cells," and "regulatory T cells." The "immunosenescence-associated secretory phenotype" has become a new hotspot, with immune checkpoint inhibitors remaining a central theme in this domain. The field of immunosenescence and immunotherapy is entering a phase of rapid development and will continue to hold significant value in future research.

Immune checkpoint inhibitors (ICIs) are a standard of care in multiple cancers. Only a minority benefits, thus, optimal use and treatment duration remain indistinct. While biomarkers albeit PD-L1 are scarce, declined performance status and cancer-related systemic inflammation detected by blood inflammatory markers such as C-reactive protein (CRP) have been linked to inferior prognosis.

We investigated the association of limited anti-PD-(L)1 treatment duration to therapy efficacy in melanoma and non-small cell lung cancer (NSCLC) patients who received therapy in a non-curative setting in Oulu University Hospital 2014-2022. Baseline prognostic factors (e.g. ECOG, CRP, and PD-L1 for NSCLC) were collected. Progression-free (PFS), overall (OS), and IO-free survival were analyzed using the Kaplan-Meier and Cox regression methods.

126 patients (NSCLC, n = 72; melanoma, n = 54) were included. Majority (n = 101) were treated in the first line. Objective response rate was 34.9%. The median (m) anti-PD-(L)1 treatment duration was 3.42 months (mo). The mPFS and mOS were 6.8 mo (CI 95% 4.4-9.3) and 19.1 mo (CI 95% 13.3-24.9). Of the baseline factors, ECOG and CRP retained their significance in multivariate analysis for PFS (HR 0.34, CI 95% 0.19-0.59; HR 0.34, CI 95% 0.22-054) and OS (HR 0.38, CI 95% 0.20-0.71; HR 0.29, CI 95% 0.17-0.49). No difference was observed in PFS (HR 1.40, CI 95% 0.68-2.90) or OS (HR 0.69, CI 95% 0.29-1.65) according to treatment duration (3-6mo vs. > 6 mo). Long median IO-free survival (10.2 months; CI 95%, 4.1-16.3) was detected.

We characterized an anti-PD-(L)1 treated advanced NSCLC and melanoma cohort in which treatment benefit occurs irrespective of treatment duration and long-term benefit is observed off-treatment.

This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.

A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.

Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.

Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.

Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.

Non-small cell lung cancer (NSCLC) has shown limited response to immunotherapy, primarily due to an immunosuppressive tumor microenvironment characterized by hypoxia and lipid raft formation, which together inhibit T-cell infiltration and function, impeding effective immune responses. To address these challenges, we developed Abstatin, an albumin-bound fluvastatin formulation that targets lipid raft disruption and mitochondrial respiration inhibition, aiming to reduce hypoxia and destabilize lipid rafts to enhance T-cell activity within the tumor. Using bioinformatics analysis, in vitro assays, and in vivo studies in both murine and humanized PDX models, we demonstrated that Abstatin reprograms the NSCLC microenvironment by concurrently lowering hypoxia levels and lipid raft integrity, thereby restoring T-cell infiltration, enhancing cytotoxic T-cell function, and ultimately improving response to Anti-PD-1 therapy. Results showed that Abstatin significantly amplifies Anti-PD-1 efficacy with minimal toxicity, indicating a favorable safety profile for clinical use. This study highlights Abstatin as a promising immunotherapy adjuvant that addresses critical barriers in NSCLC by modulating metabolic pathways linked to immune resistance. Abstatin's approach, which combines modulation of cellular metabolism with immune sensitization, broadens the potential of immunotherapy and provides a practical, scalable strategy to enhance treatment outcomes in NSCLC and potentially other tumors, offering insights into combinatory cancer therapies.

Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Pembrolizumab alone is a first-line therapeutic option for patients with metastatic non-small cell lung cancer (NSCLC) with ≥ 50% PD-L1 expression, but few data are available for elderly patients, specifically octogenarians.

This retrospective, multicenter study included all consecutive patients with metastatic NSCLC PD-L1 ≥ 50% treated with first-line pembrolizumab monotherapy between May 2017 and November 2019. Information was collected from medical files with local evaluation of therapeutic response and progression-free survival (PFS).

Among the 844 patients included, 73 (8.4%) were ≥ 80 (median: 82) years old, 74% men, 23.3% with ECOG-PS ≥ 2, 26% had ≥ 5% weight loss, PD-L1 50%-75%/≥ 75%: 45.2%/46.6%, respectively, with significantly more nonsmokers and (17.4% vs. 5.6%, P = .0002) and fewer adenocarcinomas (57.5% vs. 70.8%, P = .0217) than those < 80 years. After median follow-up of 45.7 (95% CI: 43.0-49.1) months, respective median overall survival (OS) for octogenarians versus younger patients lasted 12.0 (95% CI: 7.7-16.2) versus 23.9 (95% CI: 19.5-27.4) months (P = .0002), and median PFS for 5.0 (95% CI: 2.8-9.2) versus 8.3 (95% CI: 7.2-9.8) months (P = .039). Their respective objective response rates did not differ significantly: 42% (95% CI: 24-60) vs. 49% (95% CI: 43-54).

Based on the results of this large multicenter population, first-line pembrolizumab efficacy against NSCLCs expressing ≥ 50% PD-L1 in octogenarians seems inferior to that obtained in younger patients. The higher percentage of nonsmokers and fewer adenocarcinomas could partially explain that finding.

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the importance of implementing ATB stewardship recommendations in routine oncology practice. Microbiota-centered interventions are now being explored to treat gut dysbiosis and optimize ICI responses. Early-phase clinical trials evaluating fecal microbiota transplantation (FMT) from ICI responders or healthy donors have shown that this approach is safe and provided preliminary data on potential efficacy to overcome both primary and secondary resistance to ICI in melanoma, non-small cell lung cancer, and renal cell carcinoma. More targeted interventions including live bacterial products including Clostridium butyricum and Akkermansia massiliensis represent novel microbiome-based adjunct therapies. Likewise, dietary interventions, such as high-fiber diets, have shown promise in enhancing ICI activity. In this ASCO Educational Book, we summarize the current state-of-the-evidence of the clinical relevance of the intestinal microbiota in cancer immunotherapy and provide a practical guide for ATB stewardship.

Precision medicine according to molecularly defined subgroups offers great potential to improve outcomes for patients with metastatic lung adenocarcinoma. This study describes clinical outcomes and the impact of co-occurring genetic alterations on outcomes following stereotactic radiosurgery (SRS) among patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma.

A total of 195 patients with KRAS-mutant lung adenocarcinoma were treated with SRS for brain metastases (BMs) between 2014 and 2018 with follow-up until 2022 or death. Coprimary outcomes were median overall survival (OS) and intracranial progression-free survival (iPFS); univariable and multivariable Cox regression models and Kaplan-Meier survival analysis were used.

Median follow-up from the date of BM diagnosis was 11 months. Median OS and iPFS for the cohort were 27.7 months (95% CI, 19.7-36.8) and 22.1 months (95% CI, 16.8-48.9), respectively. Lesion-level local control at 12 and 24 months was 89.9% and 87.5%, respectively. In a multivariable Cox regression model, inferior OS was associated with coalterations in KEAP1 and STK11 (hazard ratio [HR], 1.94; 95% CI, 1.04-3.62; q = 0.087), progressive (HR, 3.41; 95% CI, 1.38-8.39; q = 0.087), and mixed response (HR, 3.52; 95% CI, 1.2-10.3; q = 0.092) extracranial disease, and 6 or more BMs at time of diagnosis (HR, 2.58; 95% CI, 1.22-6.63; q = 0.087). Positive programmed death ligand 1 status was associated with improved OS (HR, 0.57; 95% CI, 0.37-0.87; P = .01). Inferior iPFS was associated with chemotherapy before SRS (HR, 2.69; 95% CI, 1.42-5.09; q = 0.04) and age >65 years (HR, 2.21; 95% CI, 1.25-3.93; q = 0.055). KRAS G12C was not associated with differences in iPFS, OS, or type of intracranial progression event following SRS.

Coalteration of KRAS and KEAP1/STK11 was associated with inferior OS, but not iPFS. Similar outcomes were found in patients harboring KRAS G12C and non-G12C mutant non-small cell lung cancer BMs. Further understanding of molecularly characterized subgroups will be critical in driving personalized radiation therapy for patients with lung cancer BMs.

Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.

Immune checkpoint inhibitors (ICIs) have become a central part of cancer care. However, the survivorship outcomes in patients treated with ICIs are understudied. Therefore, we conducted a scoping review to evaluate the current status of the field and to establish research gaps regarding survivorship outcomes with ICIs in real-life cohorts.

We used the Web of Science, PubMed, and Embase databases to systematically filter published studies with real-life cohorts from January 1, 2010, until October 19, 2022. Studies evaluating at least one survivorship outcome in ICI-treated patients were included.

A total of 39 papers were included. Quality of life (QoL) (n = 23), toxicity burden (n = 16), and psychosocial issues (n = 9) were the most frequently evaluated survivorship outcomes. Anti-PD-1/PD-L1 monotherapy and a response to treatment were associated with better QoL. In addition, the ICIs were associated with grade 3 or higher immune-related adverse events (irAEs) in 10-15% and late/long-term irAEs in 20-30% of the survivors. Regarding psychosocial problems, over 30% of survivors showed evidence of anxiety and depression, and 30-40% of survivors reported neurocognitive impairments.

The survivors treated with ICIs have impairments in most survivorship domains. Further research is needed to gather data on the understudied survivorship outcomes like late and long-term effects, fertility, financial toxicity, and return to work in survivors treated with ICIs.

Available evidence demonstrates that a significant portion of survivors treated with ICIs have a significant toxicity burden, lower QoL than the general population, and a high rate of psychosocial problems.

Chemo-immunotherapy has become a standard of care for the first-line treatment of non-small cell lung cancer (NSCLC), but currently still lacks reliable markers to predict therapeutic efficacy and long-term response (LTR).

In this study, we retrospectively summarized the survival outcome of 319 patients with locally advanced or metastatic NSCLC who received anti-programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) based therapy from January 1st, 2018 to February 28th, 2022 at the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. Then a comprehensive analysis of the association of LTR or survival outcomes with various characteristics including clinical parameters, peripheral blood lymphocyte subsets and common gene mutations in 167 NSCLC patients who received first-line anti-PD-1 plus chemotherapy treatment was conducted. LTR was defined as progression-free survival (PFS) exceeding 24 months, while non-responders had a PFS of less than 6 months.

With a median follow-up time of 32.1 months (95% confidence interval [CI] 29.2-38.0), the median overall survival (OS) was 29.9 months (95% CI 23.6-37.5) in locally advanced or metastatic NSCLC receiving anti-PD-1/PD-L1 based treatment. Among 167 patients who received the first-line chemo-immunotherapy, 25.1% (n = 42) achieved LTR. Independent baseline predictors of LTR included age < 65 years (odds ratio [OR] = 3.22, p = 0.024), overweight or obesity (body mass index [BMI] ≥ 24 kg/m2, OR = 3.26, p = 0.020), and a C-reactive protein/albumin ratio (CAR) score < 0.07 (OR = 9.94, p = 0.039). In multivariate cox analysis, both patients with higher CAR scores of ≥ 0.07 (hazard ratio [HR] = 2.83, p = 0.016) and those who were underweight (BMI < 18.5 kg/m2) (HR = 4.52, p = 0.005) were observed with significantly shorter OS. A peripheral B cell percentage ≥ 14.5% was more prevalent among LTR patients (OR = 9.23, p = 0.045) after adjusting for age, BMI and TNM stage. Additionally, the presence of TP53 mutation (16/66) was associated with non-response to first-line chemo-immunotherapy (p = 0.048) and shorter PFS (p = 0.028) and OS (p = 0.023) outcomes in univariate analysis.

This study provides some new insights into the features and predictors significantly associated with LTR and survival in NSCLC patient receiving first-line treatment of anti-PD-1 plus chemotherapy. Those whose age < 65 years, overweight or obesity, or has a baseline CAR score < 0.07 are more likely to achieve optimal benefit from the first-line treatment of chemo-immunotherapy.

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have revolutionized cancer therapy. However, primary and secondary resistance to ICI pose significant challenges. Recent studies underscore the critical role of gut microbiota (GM) in modulating ICI efficacy by shaping host immune responses and regulating the tumor microenvironment (TME). The composition of the GM has been linked to ICI treatment outcomes, with certain microbial taxa, such as Faecalibacterium spp., Bifidobacterium spp., Eubacterium spp., Roseburia spp., and Akkermansia muciniphila, associated with favorable responses. Mechanistically, the GM affects immune responses via multiple pathways, including induction of T cell differentiation, promotion of anti- or proinflammatory cytokine environments, and enhancement of T cell priming and effector functions. Moreover, microbial-derived metabolites play a role in shaping tumor immune responses and influencing ICI efficacy. Antibiotic treatment can disrupt GM diversity and composition (gut dysbiosis), potentially diminishing ICI effectiveness. A deeper understanding of the interplay between GM, antibiotic treatment, and ICI efficacy is crucial for developing personalized therapeutic strategies to improve patient outcomes. Herein, we review current evidence on the association between specific microbial taxa and tumor immunosurveillance, the impact of antibiotics on the GM composition and immune modulation, and its implications for ICI therapy efficacy.

Non-small cell lung cancer (NSCLC) constitutes over 80% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Despite the advent of immune checkpoint inhibitors, their efficacy is limited to 27 to 45% of patients. Identifying likely treatment responders is essential for optimizing healthcare and improving quality of life. We generated multiplex immunofluorescence (mIF) images, histopathology, and RNA sequencing data from human NSCLC tissues. Through the analysis of mIF images, we characterized the spatial organization of 1.5 million cells based on the expression levels for 33 biomarkers. To enable large-scale characterization of tumor microenvironments, we developed NucSegAI, a deep learning model for automated nuclear segmentation and cellular classification in histology images. With this model, we analyzed the morphological, textural, and topological phenotypes of 45.6 million cells across 119 whole-slide images. Through unsupervised phenotype discovery, we identified specific lymphocyte phenotypes predictive of immunotherapy response. Our findings can improve patient stratification and guide selection of effective therapeutic regimens.

This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting.

This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate.

A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs.

A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.

As machine learning (ML) continuously develops in cancer diagnosis and treatment, some researchers have attempted to predict the expression of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) by ML. However, there is a lack of systematic evidence on the effectiveness of ML.

We conducted a thorough search across Embase, PubMed, the Cochrane Library, and Web of Science from inception to December 14th, 2023.A systematic review and meta-analysis was conducted to assess the value of ML for predicting PD-L1 expression in NSCLC.

Totally 30 studies with 12,898 NSCLC patients were included. The thresholds of PD-L1 expression level were < 1%, 1-49%, and ≥ 50%. In the validation set, in the binary classification for PD-L1 ≥ 1%, the pooled C-index was 0.646 (95%CI: 0.587-0.705), 0.799 (95%CI: 0.782-0.817), 0.806 (95%CI: 0.753-0.858), and 0.800 (95%CI: 0.717-0.883), respectively, for the clinical feature-, radiomics-, radiomics + clinical feature-, and pathomics-based ML models; in the binary classification for PD-L1 ≥ 50%, the pooled C-index was 0.649 (95%CI: 0.553-0.744), 0.771 (95%CI: 0.728-0.814), and 0.826 (95%CI: 0.783-0.869), respectively, for the clinical feature-, radiomics-, and radiomics + clinical feature-based ML models.

At present, radiomics- or pathomics-based ML methods are applied for the prediction of PD-L1 expression in NSCLC, which both achieve satisfactory accuracy. In particular, the radiomics-based ML method seems to have wider clinical applicability as a non-invasive diagnostic tool. Both radiomics and pathomics serve as processing methods for medical images. In the future, we expect to develop medical image-based DL methods for intelligently predicting PD-L1 expression.

The safety of administering immune checkpoint inhibitors (ICIs) after talc pleurodesis, particularly the impact of talc on the development of immune-related interstitial lung disease (ILD), remains unclear.

We retrospectively analysed patients with primary lung cancer or malignant pleural mesothelioma who received ICIs within 90 days of talc pleurodesis at facilities participating in the Niigata Lung Cancer Treatment Study Group between November 2016 and June 2023.

A total of 52 cases were included, with 17 patients (32.7 %) developing ILD following ICI administration. The median time to ILD onset after ICI administration was 62 days. The median overall survival was 6 months in patients who developed ILD and 16.4 months in those who did not (P = 0.081). Among the five patients with pre-existing interstitial changes, four (80.0 %) developed ILD after ICI administration, identifying a high-risk subgroup.

A high incidence of ILD was observed in patients who received ICI therapy after talc pleurodesis. Additionally, overall survival tended to be shorter in patients who developed ILD.

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance.

We conducted an in vivo chemical screen to identify F1929-1458, which is capable of eliciting an organism-wide response to destroy stem cell tumors in Drosophila. We then performed functional validation using a mouse colorectal cancer graft tumor model established with the CT26 cell line characterized by its high content of CSCs. Single-cell sequencing was employed to analyze alterations in the TME. Small molecule pull-down mass spectrometry, cellular thermal shift assay, drug affinity experiment, and molecular docking were utilized to identify the target of F1929-1458. An in vitro co-culture system was applied to establish that the damage-associated molecular patterns (DAMPs) released by the tumor cells are accountable for the activation of dendritic cells (DCs).

We demonstrated that F1929-1458 treatment enhanced T cell infiltration and T cell mediated tumor regression, its anti-tumor effect was nullified in nude mice and was abolished after anti-CD3 neutralizing antibody treatment. We found that F1929-1458 binds NFKB1 to activate the NF-κB signaling pathway in tumor cells. The activation further elicits cellular stress, causing tumor cells to release DAMPs (HMGB1-gDNA complex, ATP, and OxLDL). These DAMPs, in turn, stimulate the cGAS-STING and NLRP3 inflammasome pathways in DCs, resulting in the generation of type I IFNs and IL-1β. These cytokines facilitate the maturation of DCs and antigen presentation, ultimately enhancing T cell-mediated anti-tumor immunity. Additionally, we showed that the combination of F1929-1458 and the anti-PD-1 antibody exhibited a synergistic anti-tumor effect.

Our study identified a novel NFKB1 agonist that promotes anti-tumor immunity by remodeling the TME and activating DCs and that may provide a new way to overcome resistance to current anti-tumor immunotherapy in colorectal cancer.

Despite much progress in targeting the MYC oncoprotein, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa histone deacetylases (HDACs), as potential therapeutic targets. Notably, these therapeutically actionable HDAC isoforms are known augmenters of several hallmarks of cancer. Dual targeting of MYC and class IIa HDACs induces a significant reduction in viability for non-small cell lung cancer (NSCLC) cell lines with high MYC and mitochondrial activity. Additionally, combination treatment induces a robust MYC suppression with mitochondrial reactive oxygen species (ROS) elevation, which has a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal models, with subsequent molecular-correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in drug efficacy. Ultimately, we define a therapeutic approach combining MYC- and class IIa HDAC-inhibition to potentiate anti-tumor efficacy in NSCLC.

In studies evaluating the efficacy of anti-programmed cell death 1/ligand 1 immune checkpoint inhibitors (anti-PD-(L)1) among patients with non-small cell lung cancer (NSCLC), smokers tend to have better clinical outcomes than non-smokers. However, it is unclear whether NSCLC patients with co-existing chronic obstructive pulmonary disease (COPD) have better clinical outcomes than patients without COPD, regardless of smoking history. The potential correlation of COPD with an improved response to anti-PD-(L)1 was examined in a large cohort of patients with available pulmonary function test results. Patients with stage IV NSCLC who received a minimum of two doses of anti-PD-(L)1 across various treatment lines from 2015 to 2021 were enrolled. Among the 387 patients, pulmonary function test (PFT) data were available for 234 (61%), 139 (59%) of whom had spirometry diagnosed COPD. A retrospective analysis was conducted to evaluate overall survival (OS) and progression-free survival (PFS) based on the presence or absence of COPD. In the univariate analyses, both PFS and OS significantly improved among patients with COPD, compared with patients who did not have COPD (HR 0.71, 95% CI 0.56-0.89 for PFS; HR 0.69, 95% CI 0.52-0.92 for OS), regardless of smoking status. In the multivariate analyses, PFS and OS remained superior among patients with COPD (HR 0.66, 95% CI 0.51-0.85 for PFS; HR 0.63, 95% CI 0.47-0.85 for OS). Additionally, patients with milder COPD (GOLD 1/2 vs. 3/4) had better clinical outcomes than patients with more severe disease. However, neither lung distension (defined as a total lung capacity > 120%) nor pre-COPD status (defined as a diffusing capacity of lung for carbon monoxide < 70%) had a significant impact on PFS or OS. Our study, conducted in the largest cohort with available PFT data to date, showed that COPD was associated with improved survival outcomes among patients with stage IV NSCLC who received anti-PD-(L)1 treatment, regardless of smoking history. The differences were mainly driven by mild and moderate obstruction (GOLD 1 and 2). The dysregulated PD-1/PD-L1 expression that occurs in COPD may offer insights into the different outcomes and thus warrants further investigation.

Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.

Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.

Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer (mHSPC) experience disease progression to castration-resistant disease within 5 years. The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen deprivation therapy (ADT) in participants with mHSPC.

Eligible participants were aged ≥18 years with next-generation hormonal agent‒naive mHSPC. Participants were randomly assigned (1:1) to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles, with oral enzalutamide 160 mg and continuous ADT. Primary end points were radiographic progression-free survival (rPFS) and overall survival. Safety was a secondary end point.

Between March 2, 2020, and August 9, 2021, 626 participants were randomly assigned to pembrolizumab plus enzalutamide and ADT and 625 participants to placebo plus enzalutamide and ADT. At the first interim analysis, the median follow-up was 21.1 months (range, 14.8-32.0 months). rPFS was not superior with pembrolizumab versus placebo (median not reached in both arms; hazard ratio, 1.20 [95% confidence interval (CI), 0.96 to 1.49]; P = 0.9467). Median overall survival was not reached in either arm (hazard ratio, 1.16 [95% CI, 0.88 to 1.53]; not formally statistically tested per the multiplicity strategy). Grade ≥3 adverse events (AEs) and serious AEs were reported in 61.9% versus 38.1% and 40.3% versus 23.2% of participants in the pembrolizumab versus the placebo arm, respectively. Any-grade rash occurred at a higher frequency with pembrolizumab (25.1%) versus placebo (9.3%).

KEYNOTE-991 did not meet its primary end point and was stopped for futility. The addition of pembrolizumab to enzalutamide and ADT was associated with higher frequencies of grade ≥3 AEs and serious AEs than with placebo. Rash was identified as an additional safety signal with pembrolizumab plus enzalutamide and ADT.

In the phase 3 EMPOWER-Lung 1 study, first-line cemiplimab monotherapy provided significant survival benefit versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. This exploratory subgroup analysis investigated the clinical outcomes of cemiplimab treatment in patients with advanced NSCLC with brain metastases.

Patients with advanced NSCLC were randomized (1:1) to cemiplimab 350 mg every 3 weeks or four cycles of platinum doublet chemotherapy (NCT03088540). Patients with symptomatic radiotherapy-treated brain metastases were eligible to enroll. Of the 565 patients with confirmed PD-L1 expression ≥50%, 69 (12%) had brain metastases at baseline.

Patients with brain metastases who received cemiplimab had a median overall survival (OS) of 52.4 months compared with 20.7 months for those who received chemotherapy (hazard ratio [HR], 0.40; p = .0031) and a median progression-free survival (PFS) of 12.5 versus 5.3 months (HR, 0.33; p = .0002), respectively. Patients without brain metastases had a median OS of 24.3 months with cemiplimab versus 12.5 months with chemotherapy (HR, 0.63; p < .0001); their median PFS was 6.5 months versus 5.2 months (HR, 0.55; p < .0001), respectively. Cemiplimab was associated with a significant improvement in global health status/quality of life in all patients, including those with brain metastases. The cemiplimab safety profile was generally similar in all patients.

In patients with advanced NSCLC with PD-L1 ≥50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases.

Lung cancer remains a significant global health challenge, demanding innovative treatment strategies. Immune checkpoint blockade has revolutionized cancer care, leading to improved survival across advanced malignancies and has now become a standard therapy for earlier stage, resectable lung cancer. This review article consolidates the current landscape and future prospects of neoadjuvant and perioperative immunotherapy in lung cancer. The authors outline key findings from clinical trials in resectable lung cancer, including early efficacy, safety profiles, and emerging impact on disease recurrence, and overall survival. Additionally, this review elucidates the challenges encountered, including patient selection criteria, optimal treatment schedules, immune-related adverse events, and impact on surgery. This comprehensive analysis amalgamates current evidence with future directions, providing a roadmap for clinicians, researchers, and stakeholders to navigate the dynamic realm of immunotherapy for surgically resectable lung cancer.

Lung cancer is the leading cause of death worldwide. It occurs mainly in smokers, but also in 25% of cases in non-smokers. As regards metastatic stages, while immunotherapy has led to improved overall survival, smoking status may potentially influence its effectiveness. The objective of this study was to analyze its effectiveness as first-line treatment for advanced non-small cell lung cancers (NSCLC) according to patient smoking status.

This retrospective study covers all patients with stage IV NSCLC treated with first- line immunotherapy, alone or in combination, between January 2018 and 2019, in three Ile de France centers. The primary and secondary endpoints were, respectively, overall survival and progression-free survival, according to smoking status.

The analysis included 105 patients (66.7% men) of whom 38% were active smokers and 9.5% non-smokers, with adenocarcinoma in 65.7% of cases. Median OS and PFS were 17, 23.2, and 24.9 months and 4.9, 7.6, and 4 months for smokers, ex-smokers, and non-smokers respectively, without significant differences.

In this study, smoking status did not seem to modify the effectiveness of immunotherapy. Studies on a larger population are called for.

Chemoradiotherapy (CRT) followed by durvalumab (CRT → durvalumab) is standard of care to treat patients with unresectable, stage III non-small cell lung cancer (NSCLC). The RELEVANCE study was designed to provide real-world effectiveness and safety data for CRT → durvalumab in Canadian settings.

RELEVANCE was a retrospective, observational, multicenter chart review that included adult patients with unresectable, stage III NSCLC treated with CRT alone or CRT → durvalumab at 5 Canadian cancer centers. Key outcomes included treatment patterns, adverse events of special interest (AESI), and overall survival (OS).

487 patients were included (144 CRT alone; 343 CRT → durvalumab). Median follow-up was 43.1 and 35.8 months for the CRT alone and CRT → durvalumab groups, respectively. The most frequently observed regimen included radiotherapy dose 54-66 Gy and radiosensitizing carboplatin. Median treatment duration was 1.5 months (CRT alone) and 13.4 months (CRT → durvalumab), and 47 % of patients completed a full course of durvalumab. Median OS and 3-year OS rate were 21.3 months and 32 % for CRT alone and 44.6 months and 56 % for CRT → durvalumab. Exploratory analysis by programmed cell death-ligand 1 (PD-L1) expression status of the CRT → durvalumab group noted 3-year OS rates of 69 %, 44 %, and 39 % in the PD-L1 ≥ 50 % (high), 1 %-49 % (intermediate), and < 1 % (negative) populations, respectively (32 %, 38 %, and 24 % for CRT alone, respectively). PD-L1 high expression was associated with lower risk of death vs. PD-L1 negative expression (P < 0.05). The most common AESI with CRT → durvalumab was pneumonitis. Median OS for patients who completed durvalumab was not reached and was 41.3 months among patients who discontinued durvalumab due to AEs.

Results validate the treatment benefit and safety of the PACIFIC regimen in real-world Canadian settings. Among patients who received CRT → durvalumab, there was a correlation between increasing PD-L1 status and improved OS; however, shorter OS was observed in patients discontinuing durvalumab early due to AEs.

Real-world Canadian RELEVANCE study validates effectiveness and safety of durvalumab in patients with unresectable, stage III NSCLC.

Cancer progression is governed by a dynamic interplay of genetic, epigenetic, and molecular mechanisms that regulate tumor initiation, growth, metastasis, and therapy resistance. This review highlights key molecular pathways involved in oncogenesis, focusing on genetic alterations (mutations, amplifications, and translocations) in oncogenes (RAS and MYC) and tumor suppressor genes (TP53 and PTEN). Additionally, genomic instability, resulting from defective DNA repair mechanisms like mismatch repair and homologous recombination (HR), is identified as a critical factor contributing to tumor heterogeneity and clonal evolution. Epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNA regulation, further remodel chromatin structure and modulate gene expression, influencing tumor initiation, growth, metastasis, and response to treatment. Post-translational modifications, such as the attachment of a Small Ubiquitin-like Modifier (SUMO) to a target protein and ubiquitination, further influence autophagy, apoptosis, and cellular plasticity, enabling cancer cells to survive therapeutic stress. Cutting-edge technologies such as CRISPR-Cas9-mediated epigenome editing and single-cell RNA sequencing have opened new doors to understanding cellular diversity and regulatory networks in cancer. The review further examines the tumor microenvironment, including stromal remodeling, immune evasion, and hypoxia-driven signaling pathways, which are critical modulators of tumor progression and drug resistance to treatment. By integrating molecular, genetic, and epigenetic perspectives, this study underscores the crucial need for innovative, targeted therapeutic approaches to address the complexity and adaptability of cancer, thereby paving the way for more effective treatments.

Pembrolizumab is used as a first-line treatment of non-small cell lung cancer. Pneumonitis and interstitial lung disease are among the most common immune-related adverse events. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on patients with cancer treated with chemotherapy or immune checkpoint inhibitors (ICIs) is not fully known. Blocking immune checkpoints may conversely augment dysfunctional T-cell responses in severe patients and, in turn, mediate immunopathology. Here, we present a case of SARS-CoV-2 infection complicated by acute respiratory distress syndrome (ARDS) and a fibrotic-like pattern in a patient treated with pembrolizumab for lung cancer. The patient showed a dramatic clinical and radiological response after steroid therapy. Further research is needed to better understand the long-term implications of pembrolizumab therapy in patients recovering from coronavirus disease 2019 (COVID-19) and to develop evidence-based guidelines for managing these complex cases. Patients undergoing oncologic immunotherapy might benefit from early high-dose steroid treatment in cases of viral infections, such as SARS-CoV-2.