Outcome Of Immunotherapy Research Articles

Metastasis and basement membrane-related signature enhances hepatocellular carcinoma prognosis and diagnosis by integrating single-cell RNA sequencing analysis and immune microenvironment assessment

BackgroundHepatocellular carcinoma (HCC) is the most common type of primary liver cancer and second leading cause of cancer-related deaths worldwide. The heightened mortality associated with HCC is largely attributed to its propensity for metastasis, which cannot be achieved without remodeling or loss of the basement membrane (BM). Despite advancements in targeted therapies and immunotherapies, resistance and limited efficacy in late-stage HCC underscore the urgent need for better therapeutic options and early diagnostic biomarkers. Our study aimed to address these gaps by investigating and evaluating potential biomarkers to improve survival outcomes and treatment efficacy in patients with HCC.MethodIn this study, we collected the transcriptome sequencing, clinical, and mutation data of 424 patients with HCC from The Cancer Genome Atlas (TCGA) and 240 from the International Cancer Genome Consortium (ICGC) databases. We then constructed and validated a prognostic model based on metastasis and basement membrane-related genes (MBRGs) using univariate and multivariate Cox regression analyses. Five immune-related algorithms (CIBERSORT, QUANTISEQ, MCP counter, ssGSEA, and TIMER) were then utilized to examine the immune landscape and activity across high- and low-risk groups. We also analyzed Tumor Mutation Burden (TMB) values, Tumor Immune Dysfunction and Exclusion (TIDE) scores, mutation frequency, and immune checkpoint gene expression to evaluate immune treatment sensitivity. We analyzed integrin subunit alpha 3 (ITGA3) expression in HCC by performing single-cell RNA sequencing (scRNA-seq) analysis using the TISCH 2.0 database. Lastly, wound healing and transwell assays were conducted to elucidate the role of ITGA3 in tumor metastasis.ResultsPatients with HCC were categorized into high- and low-risk groups based on the median values, with higher risk scores indicating worse overall survival. Five immune-related algorithms revealed that the abundance of immune cells, particularly T cells, was greater in the high-risk group than in the low-risk group. The high-risk group also exhibited a higher TMB value, mutation frequency, and immune checkpoint gene expression and a lower tumor TIDE score, suggesting the potential for better immunotherapy outcomes. Additionally, scRNA-seq analysis revealed higher ITGA3 expression in tumor cells compared with normal hepatocytes. Wound healing scratch and transwell cell migration assays revealed that overexpression of the MBRG ITGA3 enhanced migration of HCC HepG2 cells.ConclusionThis study established a direct molecular correlation between metastasis and BM, encompassing clinical features, tumor microenvironment, and immune response, thereby offering valuable insights for predicting clinical outcomes and immunotherapy responses in HCC.

GRASLND regulates melanoma cell progression by targeting the miR-218-5p/STAM2 axis

BackgroundIncreasing evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in biological processes and are dysregulated in numerous tumors. The lncRNA GRASLND functions as an oncogene in many cancers, but its role in skin cutaneous melanoma (SKCM) requires further investigation.MethodsSiRNA transfection, wound − healing and transwell assays were performed to evaluate the effect of GRASLND on cellular function.ResultsThe present study demonstrated that GRASLND expression is increased in SKCM tissues and cell lines. The high expression of GRASLND was correlated with poor prognosis and immunotherapy outcomes. Knockdown of GRASLND significantly inhibited cell migration and invasion. In addition, we found that miR-218-5p directly binds to its binding site on GRASLND, and GRASLND and miR-218-5p demonstrate mutual inhibition. Furthermore, the miR-218-5p inhibitor partially eliminated the knockdown of GRASLND and inhibited its expression. We also demonstrated that GRASLND acts as a miR-218-5p sponge that positively regulates STAM2 expression in SKCM cells.ConclusionIn summary, these data suggest that GRASLND functions by regulating miR-218-5p/STAM2 expression, suggesting an important role for the lncRNA‒miRNA–mRNA functional network and a new potential therapeutic target for SKCM.

Machine learning-driven mast cell gene signatures for prognostic and therapeutic prediction in prostate cancer

BackgroundThe role of Mast cells has not been thoroughly explored in the context of prostate cancer's (PCA) unpredictable prognosis and mixed immunotherapy outcomes. Our research aims to employs a comprehensive computational methodology to evaluate Mast cell marker gene signatures (MCMGS) derived from a global cohort of 1091 PCA patients. This approach is designed to identify a robust biomarker to assist in prognosis and predicting responses to immunotherapy. MethodsThis study initially identified mast cell-associated biomarkers from prostate adenocarcinoma (PRAD) patients across six international cohorts. We employed a variety of machine learning techniques, including Random Forest, Support Vector Machine (SVM), Lasso regression, and the Cox Proportional Hazards Model, to develop an effective MCMGS from candidate genes. Subsequently, an immunological assessment of MCMGS was conducted to provide new insights into the evaluation of immunotherapy responses and prognostic assessments. Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and pathway analysis to explore the biological pathways and mechanisms associated with MCMGS. ResultsMCMGS incorporated 13 marker genes and was successful in segregating patients into distinct high- and low-risk categories. Prognostic efficacy was confirmed by survival analysis incorporating MCMGS scores, alongside clinical parameters such as age, T stage, and Gleason scores. High MCMGS scores were correlated with upregulated pathways in fatty acid metabolism and β-alanine metabolism, while low scores correlated with DNA repair mechanisms, homologous recombination, and cell cycle progression. Patients classified as low-risk displayed increased sensitivity to drugs, indicating the utility of MCMGS in forecasting responses to immune checkpoint inhibitors. ConclusionThe combination of MCMGS with a robust machine learning methodology demonstrates considerable promise in guiding personalized risk stratification and informing therapeutic decisions for patients with PCA.

Real-World Outcomes of Immunotherapy for Melanoma Brain Metastases in New Zealand.

Melanoma brain metastases (BMs) are associated with poor survival. Combination immune checkpoint inhibitors (ICIs) with anti-PD1 and anti-CTLA-4 are the international standard-of-care treatment. Most landmark clinical trials excluded real-world patients with symptomatic disease, poor performance status (PS), and steroid use. Despite the high incidence of melanoma in New Zealand (NZ), the only publicly funded systemic treatment is anti-PD1 monotherapy. The real-world outcomes for BMs after ICIs in NZ are unknown. Medical records of patients with melanoma BMs in seven cancer centers across NZ between September 1, 2016, and September 1, 2020, were evaluated. Clinicopathologic characteristics, treatment, intracranial (IC) tumor response rates, IC progression-free survival, and overall survival (OS) are reported. One hundred and forty-four patients received at least one dose of ICI. One hundred and thirty-three (93%) patients received anti-PD1 monotherapy. Almost a quarter of patients had poor baseline PS, 56% were symptomatic, and 33% had corticosteroids. Patients also received local therapies: 61 (42%) patients underwent surgery, 42 (29%) received whole brain radiation, and 47 (33%) received stereotactic radiation. The median OS was 15 months, and a third of patients were alive at 2 years. The toxicity of ICIs was at 28% and 15% for Common Terminology Criteria for Adverse Events grade 1-2 and 3-4 events, respectively. Of the patients who are still alive, 76% of patients remained symptomatic neurologically at last follow-up. Most patients in this NZ real-world study were symptomatic and received anti-PD1 monotherapy. Approximately one-third of treated patients are alive at 2 years, but most patients remained symptomatic. This highlights the need for more effective treatment and prospective management of their neurologic rehabilitation needs.

Microbiota composition effect on immunotherapy outcomes in colorectal cancer patients: A systematic review.

Immune checkpoint inhibitors (ICIs) have emerged as an effective treatment for colorectal cancer (CRC). Studies indicate that the composition of gut microbiota could potentially serve as a biomarker for predicting the clinical effectiveness of immune checkpoint inhibitors. Following PRISMA guidelines, the review was conducted after registering the protocol with PROSPERO. A comprehensive literature search was carried out across five databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library. Assessment tools from the National Institutes of Health (NIH) were used to gauge the quality of the studies. A total of 5,132 papers were identified, and three studies and one conference abstract published between 2017-2022 met the inclusion criteria and were summarized in a descriptive synthesis table. These four studies were in accord with the following findings, four main phyla, Firmicutes, Bacteroidata, Actinobacteria, and Verrucomicrobiota were associated with CRC patients' clinical response toward ICIs treatment. Ruminococcaceae was predominantly related to CRC patients responding to therapy, while the Micrococcaceae family was more common among the non-responders. Bacterial taxa such as Faecalibacterium and Prevotellaceae were associated with better responses to ICIs and could be predictive biomarkers. The signature of fecal microbiota with Akkermansia muciniphila and Eubacterium rectale enrichment, and Rothia mucilaginosa depletion could independently predict better response to ICIs in patients with CRC. The findings have brought attention to the notable differences in terms of richness and composition of microbiota between patients who responded positively to the treatment and those who did not. Bacterial species and families, such as Faecalibacterium, Bifidobacterium, Lachnospiraceae, Akkermansia sp., Ruminococcaceae, and Prevotellaceae, have consistently surfaced as potential indicators of immunotherapeutic responses. Furthermore, this review also emphasizes the need for additional comprehensive, multi-center studies with larger sample sizes to validate reported microbiota and expand our understanding of the role of gut microbiota in CRC ICIs therapy. PROSPERO ID: CRD42021277691.

Gold Nanocluster: A Photoelectric Converter for X-Ray-Activated Chemotherapy.

Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof-of-concept is proposed for a gold nanocluster-based strategy that utilizes X-ray irradiation to trigger the liberation of platinum (Pt)-based prodrug conjugates, thus enabling radiotherapy-directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited-state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy-directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation-mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

Unraveling the influence of TTF-1 expression on immunotherapy outcomes in PD-L1-high non-squamous NSCLC: a retrospective multicenter study.

Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population. Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching. Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02). TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression.

Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a retrospective multicohort study

Understanding co-occurrence patterns and prognostic implications of immune-related adverse events is crucial for immunotherapy management. However, previous studies have been limited by sample size and generalisability. In this study, we leveraged a multi-institutional cohort and a population-level database to investigate co-occurrence patterns of and survival outcomes after multi-organ immune-related adverse events among recipients of immune checkpoint inhibitors. In this retrospective study, we identified individuals who received immune checkpoint inhibitors between May 31, 2015, and June 29, 2022, from the Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Cancer Institute (Boston, MA, USA; MGBD cohort), and between April 30, 2010, and Oct 11, 2021, from the independent US population-based TriNetX network. We identified recipients from all datasets using medication codes and names of seven common immune checkpoint inhibitors, and patients were excluded from our analysis if they had incomplete information (eg, diagnosis and medication records) or if they initiated immune checkpoint inhibitor therapy after Oct 11, 2021. Eligible patients from the MGBD cohort were then propensity score matched with recipients of immune checkpoint inhibitors from the TriNetX database (1:2) based on demographic, cancer, and immune checkpoint inhibitor characteristics to facilitate cohort comparability. We applied immune-related adverse event identification rules to identify patients who did and did not have immune-related adverse events in the matched cohorts. To reduce the likelihood of false positives, patients diagnosed with suspected immune-related adverse events within 3 months after chemotherapy were excluded. We performed pairwise correlation analyses, non-negative matrix factorisation, and hierarchical clustering to identify co-occurrence patterns in the MGBD cohort. We conducted landmark overall survival analyses for patient clusters based on predominant immune-related adverse event factors and calculated accompanying hazard ratios (HRs) and 95% CIs, focusing on the 6-month landmark time for primary analyses. We validated our findings using the TriNetX cohort. We identified 15 246 recipients of immune checkpoint inhibitors from MGBD and 50 503 from TriNetX, of whom 13 086 from MGBD and 26 172 from TriNetX were included in our propensity score-matched cohort. Median follow-up durations were 317 days (IQR 113-712) in patients from MGBD and 249 days (91-616) in patients from TriNetX. After applying immune-related adverse event identification rules, 8704 recipients of immune checkpoint inhibitors were retained from MGBD, of whom 3284 (37·7%) had and 5420 (62·3%) did not have immune-related adverse events, and 18 162 recipients were retained from TriNetX, of whom 5538 (30·5%) had and 12 624 (69·5%) did not have immune-related adverse events. In both cohorts, positive pairwise correlations of immune-related adverse events were commonly observed. Co-occurring immune-related adverse events were decomposed into seven factors across organs, revealing seven distinct patient clusters (endocrine, cutaneous, respiratory, gastrointestinal, hepatic, musculoskeletal, and neurological). In the MGBD cohort, the patient clusters that predominantly had endocrine (HR 0·53 [95% CI 0·40-0·70], p<0·0001) and cutaneous (0·61 [0·46-0·81], p=0·0007) immune-related adverse events had favourable overall survival outcomes at the 6-month landmark timepoint, while the other clusters either had unfavourable (respiratory: 1·60 [1·25-2·03], p=0·0001) or neutral survival outcomes (gastrointestinal: 0·86 [0·67-1·10], p=0·23; musculoskeletal: 0·97 [0·78-1·21], p=0·78; hepatic: 1·20 [0·91-1·59], p=0·19; and neurological: 1·30 [0·97-1·74], p=0·074). Similar results were found in the TriNetX cohort (endocrine: HR 0·75 [95% CI 0·60-0·93], p=0·0078; cutaneous: 0·62 [0·48-0·82], p=0·0007; respiratory: 1·21 [1·00-1·46], p=0·044), except for the neurological cluster having unfavourable (rather than neutral) survival outcomes (1·30 [1·06-1·59], p=0·013). Reliably identifying the immune-related adverse event cluster to which a patient belongs can provide valuable clinical information for prognosticating outcomes of immunotherapy. These insights can be leveraged to counsel patients on the clinical impact of their individual constellation of immune-related adverse events and ultimately develop more personalised surveillance and mitigation strategies. US National Institutes of Health.

Reprogramming Tumor-Associated Macrophages with a Se-Based Core-Satellite Nanoassembly to Enhance Cancer Immunotherapy.

Tumor-associated macrophages (TAMs), as the most prevalent immune cells in the tumor microenvironment, play a pivotal role in promoting tumor development through various signaling pathways. Herein, we have engineered a Se@ZIF-8 core-satellite nanoassembly to reprogram TAMs, thereby enhancing immunotherapy outcomes. When the nanoassembly reaches the tumor tissue, selenium nanoparticles and Zn2+ are released in response to the acidic tumor microenvironment, resulting in a collaborative effort to promote the production of reactive oxygen species (ROS). The generated ROS, in turn, activate the nuclear factor κB (NF-κB) signaling pathway, driving the repolarization of TAMs from M2-type to M1-type, effectively eliminating cancer cells. Moreover, the nanoassembly can induce the immunogenic death of cancer cells through excess ROS to expose calreticulin and boost macrophage phagocytosis. The Se@ZIF-8 core-satellite nanoassembly provides a potential paradigm for cancer immunotherapy by reversing the immunosuppressive microenvironment.

Prognostic value of immunotherapy in advanced NSCLC based on baseline and dynamic changes in HALP

Immune checkpoint inhibitors (ICIs) enhance the tumor-killing ability of T-cells in non-small cell lung cancer (NSCLC), improving overall survival (OS) and revolutionizing treatment for advanced stages. However, challenges remain, such as low response rates and the lack of effective markers for selecting candidates. This study evaluated the impact of hemoglobin, albumin, and platelet (HALP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the efficacy of immunotherapy and survival outcomes in advanced NSCLC. Additionally, it aimed to develop a nomogram based on these parameters. Clinical and hematological data from NSCLC patients who received immunotherapy were analyzed. Efficacy was assessed using the immune Response Evaluation Criteria in Solid Tumors (iRECIST), and progression-free survival (PFS) and OS were evaluated. Prediction models incorporated baseline and post-treatment HALP, NLR, and PLR values. The 203 patients had a median follow-up of 16 months, a median PFS (mPFS) of seven months (6.0–8.0), while the median OS (mOS) was not reached (24.0–not available). Pretreatment PLR (PLR0) was associated with a higher disease control rate (DCR) (odds ratio [OR] = 0.258), while initial immunotherapy and NLR after four treatment cycles (NLR4C) significantly improved the objective response rate (ORR). Cox regression analysis showed that pretreatment HALP (HALP0), HALP after four cycles of treatment (HALP4C), and pretreatment NLR (NLR0) significantly impacted PFS. Additionally, HALP0, NLR0, and PLR after four treatment cycles (PLR4C) were associated with OS. The C-indices for PFS and OS were 0.823 and 0.878, respectively, indicating good predictive accuracy. HALP, NLR, and PLR at various time points effectively predicted immunotherapy response in advanced NSCLC patients, with low HALP combined with high NLR and PLR indicating a poor prognosis. These findings could serve as the basis for stratified randomized controlled trials (RCTs) in the future.

EGFR mutations induce the suppression of CD8+ T cell and anti-PD-1 resistance via ERK1/2-p90RSK-TGF-β axis in non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) patients with EGFR mutations exhibit an unfavorable response to immune checkpoint inhibitor (ICI) monotherapy, and their tumor microenvironment (TME) is usually immunosuppressed. TGF-β plays an important role in immunosuppression; however, the effects of TGF-β on the TME and the efficacy of anti-PD-1 immunotherapy against EGFR-mutated tumors remain unclear.MethodsCorresponding in vitro studies used the TCGA database, clinical specimens, and self-constructed mouse cell lines with EGFR mutations. We utilized C57BL/6N and humanized M-NSG mouse models bearing EGFR-mutated NSCLC to investigate the effects of TGF-β on the TME and the combined efficacy of TGF-β blockade and anti-PD-1 therapy. The changes in immune cells were monitored by flow cytometry. The correlation between TGF-β and immunotherapy outcomes of EGFR-mutated NSCLC was verified by clinical samples.ResultsWe identified that TGF-β was upregulated in EGFR-mutated NSCLC by EGFR activation and subsequent ERK1/2-p90RSK phosphorylation. TGF-β directly inhibited CD8+ T cell infiltration, proliferation, and cytotoxicity both in vitro and in vivo, but blocking TGF-β did not suppress the growth of EGFR-mutated tumors in vivo. Anti-TGF-β antibody combined with anti-PD-1 antibody significantly inhibited the proliferation of recombinant EGFR-mutated tumors in C57BL/6N mice, which was superior to their monotherapy. Mechanistically, the combination of anti-TGF-β and anti-PD-1 antibodies significantly increased the infiltration of CD8+ T cells and enhanced the anti-tumor function of CD8+ T cells. Moreover, we found that the expression of TGF-β1 in EGFR-TKI resistant cell lines was significantly higher than that in parental cell lines. The combination of anti-TGF-β and nivolumab significantly inhibited the proliferation of EGFR-TKI resistant tumors in humanized M-NSG mice and prolonged their survival.ConclusionsOur results reveal that TGF-β expression is upregulated in NSCLC with EGFR mutations through the EGFR-ERK1/2-p90RSK signaling pathway. High TGF-β expression inhibits the infiltration and anti-tumor function of CD8+ T cells, contributing to the “cold” TME of EGFR-mutated tumors. Blocking TGF-β can reshape the TME and enhance the therapeutic efficacy of anti-PD-1 in EGFR-mutated tumors, which provides a potential combination immunotherapy strategy for advanced NSCLC patients with EGFR mutations.Graphical

EBF1-COX4I2 signaling axis promotes a myofibroblast-like phenotype in cancer-associated fibroblasts (CAFs) and is associated with an immunosuppressive microenvironment

Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes.

Evasion of the Immune System by Glioblastoma Multiforme: An Obstacle to Achieving Effective Therapies

Glioblastoma multiforme (GBM), a highly aggressive and malignant form of brain cancer, continues to pose a significant challenge in the field of oncology. Despite ongoing advancements in treatment strategies, the prognosis for GBM patients remains grim, with a 5-year survival rate hovering around 5%. The management of GBM involves multiple therapeutic approaches, including immunotherapy, but optimal treatment outcomes in terms of overcoming tumor recurrence and resistance have not been achieved. A key factor contributing to therapy resistance and the progression of GBM is the tumor's ability to evade the immune system, referred to as immune escape from cancer. This phenomenon reflects the tumor cells' efforts to adapt and survive the body's immune response. The release and expression of molecules like TGF-ß, IL-10, PD-L1, and NKG2DL by GBM cells impact the activation, recognition, and elimination of tumor cells by the immune system. Additionally, the involvement of cells such as MDSCs, Tregs, and TAMs plays a role in inhibiting the immune system's function, thereby promoting the development of GBM cells. A better comprehension of GBM's immune escape, supported by technological advances, will significantly aid in the future management of GBM patients' treatment.Keywords: glioblastoma multiforme, GBM, cancer immunity, immune evasion, immune escape, immunotherapy

A recent patent in allergy & immunology: Biomarkers on allergen-specific memory B cells to predict allergen immunotherapy outcome.

A recent patent in allergy & immunology: Biomarkers on allergen-specific memory B cells to predict allergen immunotherapy outcome.

Gastric cancer fibroblasts affect the effect of immunotherapy and patient prognosis by inducing micro-vascular production.

Immunotherapy is critical for treating many cancers, and its therapeutic success is linked to the tumor microenvironment. Although anti-angiogenic drugs are used to treat gastric cancer (GC), their efficacy remains limited. Cancer-associated fibroblast (CAF)-targeted therapies complement immunotherapy; however, the lack of CAF-specific markers poses a challenge. Therefore, we developed a CAF angiogenesis prognostic score (CAPS) system to evaluate prognosis and immunotherapy response in patients with GC, aiming to improve patient stratification and treatment efficacy. We assessed patient-derived GC CAFs for promoting angiogenesis using EdU, cell cycle, apoptosis, wound healing, and angiogenesis analysis. We then identified CAF-angiogenesis-associated differentially-expressed genes, leading to the development of CAPS, which included THBS1, SPARC, EDNRA, and VCAN. We used RT-qPCR to conduct gene-level validation, and eight GEO datasets and the HPA database to validate the CAPS system at the gene and protein levels. Six independent GEO datasets were utilized for validation. Overall survival time was shorter in the high- than the low-CAPS group. Immune microenvironment and immunotherapy response analysis showed that the high-CAPS group had a greater tendency toward immune escape and reduced immunotherapy efficacy than the low-CAPS group. CAPS is closely associated with GC prognosis and immunotherapy outcomes. It is therefore an independent predictor of GC prognosis and immunotherapy efficacy.

Lack of Clinically Significant Relationships of Age or Body Mass Index with Merkel Cell Carcinoma Immunotherapy Outcomes.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a high risk of metastasis. The development of anti-PD-1/PD-L1 immunotherapy has improved outcomes for advanced MCC, yet about 50% of such patients do not achieve durable responses. This study analyzed the effects of age and body mass index (BMI) on immunotherapy response in 183 advanced MCC patients from a single-center longitudinal database. Using Fine-Gray or Cox regression models, treatment response, progression-free survival (PFS), MCC-specific survival, and overall survival (OS) were evaluated. Age showed a significant non-linear relationship with treatment response (p = 0.04), with patients much older or younger than 70 years less likely to respond. However, age was not significantly associated with PFS (p = 0.21), MCC-specific survival (p = 0.72), or OS (p = 0.36). Similarly, BMI was not significantly correlated with treatment response (p = 0.41), PFS (p = 0.52), MCC-specific survival (p = 0.78), or OS (p = 0.71). Unlike previous studies suggesting that obesity and advanced age improve outcomes in other cancers, these associations were not observed in MCC. These findings suggest that age and BMI should not influence eligibility for immunotherapy in MCC patients, emphasizing the importance of unbiased patient selection for this treatment.

The Role of Immunotherapy in the Management of Esophageal Cancer in Patients Treated with Neoadjuvant Chemoradiation: An Analysis of the National Cancer Database.

The current National Comprehensive Cancer Network advises neoadjuvant chemoradiotherapy followed by surgery for locally advanced cases of esophageal cancer. The role of immunotherapy in this context is under heavy investigation. Patients with esophageal adenocarcinoma were identified in the National Cancer Database (NCDB) from 2004 to 2019. Three groups were generated as follows: (a) no immunotherapy, (b) neoadjuvant immunotherapy, and (c) adjuvant immunotherapy. Overall survival was evaluated using the Kaplan-Meier method and Cox proportional hazard analysis, adjusting for previously described risk factors for mortality. Of the total 14,244 patients diagnosed with esophageal adenocarcinoma who received neoadjuvant chemoradiation, 14,065 patients did not receive immunotherapy, 110 received neoadjuvant immunotherapy, and 69 received adjuvant immunotherapy. When adjusting for established risk factors, adjuvant immunotherapy was associated with significantly improved survival compared to no immunotherapy and neoadjuvant immunotherapy during a median follow-up period of 35.2 months. No difference was noted among patients who received no immunotherapy vs. neoadjuvant immunotherapy in the same model. In this retrospective analysis of the NCDB, receiving adjuvant immunotherapy offered a significant survival advantage compared to no immunotherapy and neoadjuvant immunotherapy in the treatment of esophageal adenocarcinoma. The addition of neoadjuvant immunotherapy to patients treated with neoadjuvant chemoradiation did not improve survival in this cohort. Further studies are warranted to investigate the long-term outcomes of immunotherapy in esophageal cancer.

Deciphering Regulatory T-Cell Dynamics in Cancer Immunotherapy: Mechanisms, Implications, and Therapeutic Innovations.

This Review explores how tumor-associated regulatory cells (Tregs) affect cancer immunotherapy. It shows how Tregs play a role in keeping the immune system in check, how cancers grow, and how well immunotherapy work. Tregs use many ways to suppress the immune system, and these ways are affected by the tumor microenvironment (TME). New approaches to cancer therapy are showing promise, such as targeting Treg checkpoint receptors precisely and using Fc-engineered antibodies. It is important to tailor treatments to each patient's TME in order to provide personalized care. Understanding Treg biology is essential for creating effective cancer treatments and improving the long-term outcomes of immunotherapy.

PP01.23 Plasma cell-free RNA PD-L1 or Tissue PD-L1 Protein Expression and Immunotherapy Outcomes in Advanced Non-Small Cell Lung Cancer

PP01.23 Plasma cell-free RNA PD-L1 or Tissue PD-L1 Protein Expression and Immunotherapy Outcomes in Advanced Non-Small Cell Lung Cancer

Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital.

Despite promising outcomes of first-line immunotherapy with or without chemotherapy in advanced non-small cell lung cancer (NSCLC), limited accessibility due to reimbursement was remain the problem in low to middle income countries. This study aimed to evaluate real-world effectiveness of immunotherapy in patients with advanced NSCLC in Northern Thailand. A retrospective, single-centered cohort, was conducted. Patients with advanced NSCLC who underwent PD-L1 testing (excluding EGFR and ALK mutations) and were treated with immunotherapy or without chemotherapy or chemotherapy alone were included. The primary end point was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events. A total of 123 patients, of which 21 patients received immunotherapy-based regimen and 102 patients received chemotherapy alone. The median PFS was 11.9 months in immunotherapy-based group compared to 5.93 months in the chemotherapy group, with a. hazard ratio (HR) of 0.4 (95% confidence interval [CI], 0.23 to 0.68; p = 0.001). Similarly, the median OS was 26.68 months in the immunotherapy-based group and 11.21 months in the chemotherapy group, with HR of 0.42 (95% CI 0.22-0.8; p = 0.009). ORRs were significantly higher in the immunotherapy-based group, with 65% of patients showing a response compared to 32% in the chemotherapy group (p = 0.006). The result of this real-world study in patients with advanced stage NSCLC indicate that first-line immunotherapy-based regimen was associated with significantly greater PFS, OS, and ORR with a safety profile consistent with pivotal studies.