Pub Date : 2024-05-01Epub Date: 2024-02-19DOI: 10.1097/CJI.0000000000000502
Xianmei Lv, Gaochen Lan, Qiusheng Guo
The correlation between triple-negative breast cancer (TNBC) and genes related to immunity and cancer stemness, particularly shared genes, remains unclear. This study aimed to investigate the correlation of immunity and cancer stemness with the molecular subtyping and survival rates in TNBC using bioinformatics approaches. Differential gene analysis was conducted to identify TNBC-associated differentially expressed genes (DEGs). Cancer stem cell (CSC)-related genes were obtained using weighted gene coexpression network analysis. Immune-related gene sets were retrieved from the literature. Venn analysis was performed to identify the shared DEGs between immunity and cancer stemness in TNBC. Cluster analysis and survival analysis based on the expression of these genes were conducted to identify TNBC subtypes with significant survival differences. A total of 5259 TNBC-associated DEGs, 2214 CSC-related genes, 1793 immune-related genes, and 44 shared DEGs between immunity and cancer stemness were obtained. Among them, 3 shared DEGs were closely associated with TNBC survival rates ( P <0.05). Cluster and survival analyses revealed that among 3 subtypes, cluster2 exhibited the best survival rate, and cluster3 showed the worst survival rate ( P <0.05). Dendritic cells were highly infiltrated in cluster2, while plasma cells and resting mast cells were highly infiltrated in cluster3 ( P <0.05). Genes shared by immunity and cancer stemness were capable of classifying TNBC samples. TNBC patients of different subtypes exhibited significant differences in immune profiles, genetic mutations, and drug sensitivity. These findings could provide new insights into the pathogenesis of TNBC, the immune microenvironment, and the selection of therapeutic targets for drug treatment.
{"title":"Identification of Subtypes in Triple-negative Breast Cancer Based on Shared Genes Between Immunity and Cancer Stemness.","authors":"Xianmei Lv, Gaochen Lan, Qiusheng Guo","doi":"10.1097/CJI.0000000000000502","DOIUrl":"10.1097/CJI.0000000000000502","url":null,"abstract":"<p><p>The correlation between triple-negative breast cancer (TNBC) and genes related to immunity and cancer stemness, particularly shared genes, remains unclear. This study aimed to investigate the correlation of immunity and cancer stemness with the molecular subtyping and survival rates in TNBC using bioinformatics approaches. Differential gene analysis was conducted to identify TNBC-associated differentially expressed genes (DEGs). Cancer stem cell (CSC)-related genes were obtained using weighted gene coexpression network analysis. Immune-related gene sets were retrieved from the literature. Venn analysis was performed to identify the shared DEGs between immunity and cancer stemness in TNBC. Cluster analysis and survival analysis based on the expression of these genes were conducted to identify TNBC subtypes with significant survival differences. A total of 5259 TNBC-associated DEGs, 2214 CSC-related genes, 1793 immune-related genes, and 44 shared DEGs between immunity and cancer stemness were obtained. Among them, 3 shared DEGs were closely associated with TNBC survival rates ( P <0.05). Cluster and survival analyses revealed that among 3 subtypes, cluster2 exhibited the best survival rate, and cluster3 showed the worst survival rate ( P <0.05). Dendritic cells were highly infiltrated in cluster2, while plasma cells and resting mast cells were highly infiltrated in cluster3 ( P <0.05). Genes shared by immunity and cancer stemness were capable of classifying TNBC samples. TNBC patients of different subtypes exhibited significant differences in immune profiles, genetic mutations, and drug sensitivity. These findings could provide new insights into the pathogenesis of TNBC, the immune microenvironment, and the selection of therapeutic targets for drug treatment.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-01-17DOI: 10.1097/CJI.0000000000000501
Arman Zereshkian, Ruaa Shafi, Gregory R Pond, Sebastien J Hotte
The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic/advanced squamous cell carcinomas of the head and neck (SCCHN). We evaluated the outcomes of SCCHN patients in Ontario, Canada, treated with nivolumab through retrospective review of the provincial treatment registry. Kaplan-Meier method was used to estimate overall survival (OS) and Cox regression to evaluate the prognostic effect of selected factors. Nivolumab was used as second-line therapy after disease relapse for curative-intent platinum chemotherapy (PC) (indication 1-I1), as second-line therapy post-PC in noncurative intent (indication 2-I2), and as first-line therapy in noncurative intent due to contraindication for PC (indication 3-I3). The median OS for patients treated with nivolumab was 5.8 months (95% CI: 4.5-7.3), and the 1-year OS was 28.4% (CI: 2.10-36.1). When patients with I3 were excluded to match inclusion criteria for CheckMate-141, median OS was 4.8 months (CI: 3.6-6.7) with 1-year OS of 21.8% (14.4-30.1). Patients with lower body surface area (BSA) (<1.81) had a median OS of 3.9 months (CI: 3.1-6.7) versus 9.0 months (CI: 6.5-14.8) in those with higher BSA, hazard ratio (HR)=0.12 (CI: 0.04-0.39, P <0.001). Patients receiving nivolumab for I1 had a median OS of 7.2 months (CI 3.8-9.8) versus 11.9 months (CI: 6.2-not reached) for I3, HR=1.73 (CI: 0.94-3.16). Patients receiving nivolumab for I2 had a median OS of 3.9 months (CI: 2.9-5.4) as compared with I3, HR=3.27 (CI: 1.80-5.94). Real-world analysis of patients with advanced/metastatic SCCHN in Ontario, Canada, treated with nivolumab demonstrates poorer median OS compared with CheckMate-141 trial. Lower BSA was a predictor of poorer median OS.
{"title":"Nivolumab in Squamous Cell Carcinomas of the Head and Neck (SCCHN): A Real-world Outcome Study in Ontario, Canada.","authors":"Arman Zereshkian, Ruaa Shafi, Gregory R Pond, Sebastien J Hotte","doi":"10.1097/CJI.0000000000000501","DOIUrl":"10.1097/CJI.0000000000000501","url":null,"abstract":"<p><p>The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic/advanced squamous cell carcinomas of the head and neck (SCCHN). We evaluated the outcomes of SCCHN patients in Ontario, Canada, treated with nivolumab through retrospective review of the provincial treatment registry. Kaplan-Meier method was used to estimate overall survival (OS) and Cox regression to evaluate the prognostic effect of selected factors. Nivolumab was used as second-line therapy after disease relapse for curative-intent platinum chemotherapy (PC) (indication 1-I1), as second-line therapy post-PC in noncurative intent (indication 2-I2), and as first-line therapy in noncurative intent due to contraindication for PC (indication 3-I3). The median OS for patients treated with nivolumab was 5.8 months (95% CI: 4.5-7.3), and the 1-year OS was 28.4% (CI: 2.10-36.1). When patients with I3 were excluded to match inclusion criteria for CheckMate-141, median OS was 4.8 months (CI: 3.6-6.7) with 1-year OS of 21.8% (14.4-30.1). Patients with lower body surface area (BSA) (<1.81) had a median OS of 3.9 months (CI: 3.1-6.7) versus 9.0 months (CI: 6.5-14.8) in those with higher BSA, hazard ratio (HR)=0.12 (CI: 0.04-0.39, P <0.001). Patients receiving nivolumab for I1 had a median OS of 7.2 months (CI 3.8-9.8) versus 11.9 months (CI: 6.2-not reached) for I3, HR=1.73 (CI: 0.94-3.16). Patients receiving nivolumab for I2 had a median OS of 3.9 months (CI: 2.9-5.4) as compared with I3, HR=3.27 (CI: 1.80-5.94). Real-world analysis of patients with advanced/metastatic SCCHN in Ontario, Canada, treated with nivolumab demonstrates poorer median OS compared with CheckMate-141 trial. Lower BSA was a predictor of poorer median OS.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2024-01-29DOI: 10.1097/CJI.0000000000000504
Ye Sul Jeung, June Young Chun, Beom Kyu Choi, Seog Yun Park, Hyun-Ju Lim, Jong Woong Park, Ji-Youn Han, Youngjoo Lee
Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.
{"title":"Infection-related Hospitalizations During Immune Checkpoint Inhibitor Treatment Without Immunosuppressants.","authors":"Ye Sul Jeung, June Young Chun, Beom Kyu Choi, Seog Yun Park, Hyun-Ju Lim, Jong Woong Park, Ji-Youn Han, Youngjoo Lee","doi":"10.1097/CJI.0000000000000504","DOIUrl":"10.1097/CJI.0000000000000504","url":null,"abstract":"<p><p>Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01Epub Date: 2023-12-19DOI: 10.1097/CJI.0000000000000500
Katherine G Akers, Sabine Oskar, Bin Zhao, Andrew M Frederickson, Ashwini Arunachalam
The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the development of new targeted therapies and immunotherapies. However, the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in advanced or metastatic patients with NSCLC whose tumors harbor BRAF V600E mutation, HER2/ERBB2 alteration, MET exon 14 skipping mutation, or RET rearrangement is not completely understood. A systematic literature review was performed to summarize evidence from clinical trials and observational studies on objective response rate, progression-free survival, and overall survival in patients whose tumors express these biomarkers and who were treated with PD-1/PD-L1 inhibitors. Searches of Embase, MEDLINE, conference abstracts, and a clinical trial registry identified a total of 12 unique studies: 4 studies included patients with BRAF V600E mutation, 6 studies included patients with HER2/ERBB2 alteration, 7 studies included patients with MET exon 14 skipping mutation, and 5 studies included patients with RET rearrangement. Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.
{"title":"Clinical Outcomes of PD-1/PD-L1 Inhibitors Among Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With BRAF, ERBB2/HER2, MET , or RET Alterations: A Systematic Literature Review.","authors":"Katherine G Akers, Sabine Oskar, Bin Zhao, Andrew M Frederickson, Ashwini Arunachalam","doi":"10.1097/CJI.0000000000000500","DOIUrl":"10.1097/CJI.0000000000000500","url":null,"abstract":"<p><p>The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the development of new targeted therapies and immunotherapies. However, the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in advanced or metastatic patients with NSCLC whose tumors harbor BRAF V600E mutation, HER2/ERBB2 alteration, MET exon 14 skipping mutation, or RET rearrangement is not completely understood. A systematic literature review was performed to summarize evidence from clinical trials and observational studies on objective response rate, progression-free survival, and overall survival in patients whose tumors express these biomarkers and who were treated with PD-1/PD-L1 inhibitors. Searches of Embase, MEDLINE, conference abstracts, and a clinical trial registry identified a total of 12 unique studies: 4 studies included patients with BRAF V600E mutation, 6 studies included patients with HER2/ERBB2 alteration, 7 studies included patients with MET exon 14 skipping mutation, and 5 studies included patients with RET rearrangement. Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138805482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With the development of immune checkpoints inhibitors (ICIs), immunotherapy has recently taken center stage in cancer treatment. Dendritic cells exert complicated and important functions in antitumor immunity. This study aims to construct a novel dendritic cell marker gene signature (DCMGS) to predict the prognosis and immunotherapy response of lung adenocarcinoma (LUAD). DC marker genes in LUAD were identified by analysis of single-cell RNA sequencing data. 6 genes (G0S2, KLF4, ALDH2, IER3, TXN, CD69) were screened as the most prognosis-related genes for constructing DCMGS on a training cohort from TCGA data set. Patients were divided into high-risk and low-risk groups by DCMGS risk score based on overall survival time. Then, the predictive ability of the risk model was validated in 6 independent cohorts. DCMGS was verified to be an independent prognostic factor in multivariate analysis. Furthermore, we performed pathway enrichment analysis to explore possible biological mechanisms of the powerful predictive ability of DCMGS, and immune cell infiltration landscape and inflammatory activities were exhibited to reflect the immune profile. Notably, we bridged DCMGS with expression of immune checkpoints and TCR/BCR repertoire diversity that can inflect immunotherapy response. Finally, the predictive ability of DCMGS in immunotherapy response was also validated by 2 cohorts that had received immunotherapy. As a result, the patients with lower DCMGS risk scores showed a better prognosis and immunotherapy response. In conclusion, DCMGS was suggested to be a promising prognostic indicator for LUAD and a desirable predictor for immunotherapy response.
{"title":"Comprehensive Analysis of a Dendritic Cell Marker Genes Signature to Predict Prognosis and Immunotherapy Response in Lung Adenocarcinoma.","authors":"Peng Song, Yuan Li, Moyan Zhang, Baihan Lyu, Yong Cui, Shugeng Gao","doi":"10.1097/CJI.0000000000000521","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000521","url":null,"abstract":"<p><p>With the development of immune checkpoints inhibitors (ICIs), immunotherapy has recently taken center stage in cancer treatment. Dendritic cells exert complicated and important functions in antitumor immunity. This study aims to construct a novel dendritic cell marker gene signature (DCMGS) to predict the prognosis and immunotherapy response of lung adenocarcinoma (LUAD). DC marker genes in LUAD were identified by analysis of single-cell RNA sequencing data. 6 genes (G0S2, KLF4, ALDH2, IER3, TXN, CD69) were screened as the most prognosis-related genes for constructing DCMGS on a training cohort from TCGA data set. Patients were divided into high-risk and low-risk groups by DCMGS risk score based on overall survival time. Then, the predictive ability of the risk model was validated in 6 independent cohorts. DCMGS was verified to be an independent prognostic factor in multivariate analysis. Furthermore, we performed pathway enrichment analysis to explore possible biological mechanisms of the powerful predictive ability of DCMGS, and immune cell infiltration landscape and inflammatory activities were exhibited to reflect the immune profile. Notably, we bridged DCMGS with expression of immune checkpoints and TCR/BCR repertoire diversity that can inflect immunotherapy response. Finally, the predictive ability of DCMGS in immunotherapy response was also validated by 2 cohorts that had received immunotherapy. As a result, the patients with lower DCMGS risk scores showed a better prognosis and immunotherapy response. In conclusion, DCMGS was suggested to be a promising prognostic indicator for LUAD and a desirable predictor for immunotherapy response.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140870433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1097/CJI.0000000000000522
Janmesh D Patel, Vincent J Pozorski, Nika Tavberidze, Darya G Buehler, Wei Huang, Daniel D Bennett, Vincent T. Ma
SUMMARY Standard of care treatment for metastatic cutaneous adnexal carcinomas is not well established. In this case report, we highlight the successful use of anti-programmed cell death protein 1 (anti-PD-1) therapy in treating a patient with low tumor mutation burden, microsatellite stable, high programmed death-ligand 1 (PD-L1) gene expression, metastatic primary cutaneous adnexal carcinoma with significant radiographic, and circulating tumor DNA response with durable benefit. Immune checkpoint inhibitors hold promise as a future treatment option in rare instances of metastatic disease from primary skin adnexal carcinoma. Further studies are needed to identify better immune checkpoint inhibitor predictive biomarkers for rare, advanced-stage non-melanoma skin cancers.
{"title":"Successful Treatment of Metastatic Primary Cutaneous Adnexal Carcinoma With a PD-1 Inhibitor.","authors":"Janmesh D Patel, Vincent J Pozorski, Nika Tavberidze, Darya G Buehler, Wei Huang, Daniel D Bennett, Vincent T. Ma","doi":"10.1097/CJI.0000000000000522","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000522","url":null,"abstract":"SUMMARY\u0000Standard of care treatment for metastatic cutaneous adnexal carcinomas is not well established. In this case report, we highlight the successful use of anti-programmed cell death protein 1 (anti-PD-1) therapy in treating a patient with low tumor mutation burden, microsatellite stable, high programmed death-ligand 1 (PD-L1) gene expression, metastatic primary cutaneous adnexal carcinoma with significant radiographic, and circulating tumor DNA response with durable benefit. Immune checkpoint inhibitors hold promise as a future treatment option in rare instances of metastatic disease from primary skin adnexal carcinoma. Further studies are needed to identify better immune checkpoint inhibitor predictive biomarkers for rare, advanced-stage non-melanoma skin cancers.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SUMMARY Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.
摘要免疫细胞因子是一种很有前景的癌症免疫治疗方法。抗血管内皮生长因子受体2-干扰素α(IFNα)可抑制结直肠癌(CRC)的生长,并增强肿瘤微环境中 CD8+ T 细胞的浸润,具有巨大的临床转化潜力。然而,抗血管内皮生长因子受体2-IFNα如何招募T细胞的机制尚未阐明。在这里,我们证实了抗血管内皮生长因子受体2-IFNα抑制了癌症转移并增强了CD8+ T细胞浸润。RNA 测序发现,转移性 CRC 细胞中的 CCL5 转录激活与 T 细胞浸润相关。IFNα而非抗血管内皮生长因子受体2能进一步上调肿瘤中的CCL5。在免疫功能正常的小鼠中,IFNα和抗血管内皮生长因子受体2-IFNα都能通过上调CCL5增加肿瘤浸润CD8+ T细胞亚群。敲除肿瘤细胞中的 CCL5 可减轻 CD8+ T 细胞的浸润,并抑制抗血管内皮生长因子受体 2-IFNα治疗的抗肿瘤效果。因此,我们认为 CCL5 的上调是 IFNα 和基于 IFNα 的免疫细胞因子疗法增强 CD8+ T 细胞浸润转移性 CRC 的关键。这些发现可能有助于开发与 IFNα 相关的免疫细胞因子,用于治疗浸润较少的肿瘤。
{"title":"Anti-VEGFR2-Interferon α Promotes the Infiltration of CD8+ T Cells in Colorectal Cancer by Upregulating the Expression of CCL5.","authors":"Linhua Huang, Rui Gao, Lidi Nan, Jingyao Qi, Siyu Yang, Shuai Shao, Jiajun Xie, Mingzhu Pan, Tianquan Qiu, Juan Zhang","doi":"10.1097/CJI.0000000000000516","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000516","url":null,"abstract":"SUMMARY\u0000Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1097/CJI.0000000000000520
N. Horesh, S. Emile, Z. Garoufalia, R. Gefen, Peige P. Zhou, Arun Nagarajan, S. Wexner
SUMMARY Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P<0.001), more often male (57.3% vs. 50.7%, P<0.001), had more private insurance (44.1% vs. 33.7%; P<0.001), had more left-sided tumors (49.5% vs. 39.1%; P<0.001) and liver metastasis (80.2% vs. 61.7%; P<0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P<0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P=0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P=0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P=0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P=0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.
摘要用于癌症全身治疗的免疫疗法为晚期恶性肿瘤的治疗提供了新的可能性。尽管取得了令人鼓舞的初步结果,但有关结肠癌免疫疗法疗效的证据仍然缺乏。因此,我们旨在评估免疫疗法对晚期结肠癌患者的短期和长期疗效。我们在美国国家癌症数据库中搜索了2010年至2019年期间III-IV期结肠腺癌患者。采用倾向评分匹配法将队列分为两组:接受免疫疗法的患者和对照组。主要结局指标为总生存期(OS)。在研究期间,共有23778名III-IV期结肠腺癌患者接受了免疫疗法治疗,而对照组有114753人。与对照组相比,接受免疫疗法治疗的患者更年轻(中位年龄 61 岁对 67 岁;P<0.001)、更多为男性(57.3% 对 50.7%,P<0.001)、有更多私人保险(44.1% 对 33.7%;P<0.001)、有更多左侧肿瘤(49.5% 对 39.1%;P<0.001)和肝转移(80.2% 对 61.7%;P<0.001)。免疫治疗患者接受标准化疗的比例更高(49.8% 对 41.6%;P<0.001)。经过倾向分数匹配后,免疫治疗组的平均OS明显短于对照组(34.7个月 vs. 36.2个月;P=0.008)。Cox回归分析表明,免疫疗法与死亡率风险增加有关(HR:1.1;95% CI:1.02-1.18;P=0.005)。与对照组相比,接受免疫疗法的患者的90天死亡率较低(2.3% vs. 3.6%;P=0.004),但两组患者的30天死亡率相当(0.7% vs. 0.8%;P=0.76)。免疫疗法没有改善III-IV期结肠癌患者的OS。
{"title":"Immunotherapy in Stage III-IV Colon Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.","authors":"N. Horesh, S. Emile, Z. Garoufalia, R. Gefen, Peige P. Zhou, Arun Nagarajan, S. Wexner","doi":"10.1097/CJI.0000000000000520","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000520","url":null,"abstract":"SUMMARY\u0000Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P<0.001), more often male (57.3% vs. 50.7%, P<0.001), had more private insurance (44.1% vs. 33.7%; P<0.001), had more left-sided tumors (49.5% vs. 39.1%; P<0.001) and liver metastasis (80.2% vs. 61.7%; P<0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P<0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P=0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P=0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P=0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P=0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140686358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SUMMARY Taurine (Tau) has been found to inhibit triple-negative breast cancer (TNBC) invasion and metastasis. However, its effect on tumor-promoting macrophages and tumor suppressor macrophages in breast cancer progression remains unknown. In this study, we investigated the effects of Tau on macrophage polarization and its role in TNBC cell growth, invasion, and metastasis. We induced human THP-1 monocytes to differentiate into M2 macrophages through exogenous addition of interleukin-4. We used the TNBC cell lines MDA-MB-231 and BT-549 cultured in a conditioned medium from M2 macrophages to investigate the effect of Tau on tumor growth and invasion. We analyzed macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression by quantitative polymerase chain reaction. We also detected the PTEN-PI3K/Akt/mTOR signaling pathway that mediates M1 macrophage to suppress tumor invasion using western blotting. Our results showed that Tau inhibits breast cancer metastasis to the lungs in vivo and cell invasion by altering the polarization of tumor-associated macrophage in vitro. In addition, Tau can up-regulate PTEN expression, suppress the PI3K-Akt signaling pathway, and promote the M1 polarization of macrophages, which ultimately inhibits the metastasis of TNBC cells. Our findings suggest that Tau inhibits the activation of the PI3K-Akt-mTOR signaling pathway by up-regulating PTEN, promotes the proportion of M1 macrophages in tumor-associated macrophage, and suppresses the invasion and metastasis of TNBC. This provides a potential therapeutic approach to influence cancer progression and metastasis.
摘要已发现牛磺酸(Tau)可抑制三阴性乳腺癌(TNBC)的侵袭和转移。然而,它对乳腺癌进展过程中肿瘤促进巨噬细胞和肿瘤抑制巨噬细胞的影响仍然未知。在本研究中,我们研究了 Tau 对巨噬细胞极化的影响及其在 TNBC 细胞生长、侵袭和转移中的作用。我们通过外源性添加白细胞介素-4诱导人THP-1单核细胞分化为M2巨噬细胞。我们使用在M2巨噬细胞条件培养基中培养的TNBC细胞系MDA-MB-231和BT-549来研究Tau对肿瘤生长和侵袭的影响。我们通过定量聚合酶链反应分析了巨噬细胞亚群分布、M1和M2巨噬细胞相关标记物以及mRNA表达。我们还利用Western印迹技术检测了介导M1巨噬细胞抑制肿瘤侵袭的PTEN-PI3K/Akt/mTOR信号通路。我们的研究结果表明,Tau能在体内抑制乳腺癌向肺部的转移,并在体外通过改变肿瘤相关巨噬细胞的极化来抑制细胞侵袭。此外,Tau还能上调PTEN的表达,抑制PI3K-Akt信号通路,促进巨噬细胞的M1极化,最终抑制TNBC细胞的转移。我们的研究结果表明,Tau通过上调PTEN抑制PI3K-Akt-mTOR信号通路的激活,促进肿瘤相关巨噬细胞中M1巨噬细胞的比例,抑制TNBC的侵袭和转移。这为影响癌症进展和转移提供了一种潜在的治疗方法。
{"title":"Taurine Inhibits Lung Metastasis in Triple-Negative Breast Cancer by Modulating Macrophage Polarization Through PTEN-PI3K/Akt/mTOR Pathway.","authors":"Yufeng Lin, Yongtong Huang, Yifan Zheng, Wanting Chen, Yongcheng Zhang, Yongxia Yang, Wenbin Huang","doi":"10.1097/CJI.0000000000000518","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000518","url":null,"abstract":"SUMMARY\u0000Taurine (Tau) has been found to inhibit triple-negative breast cancer (TNBC) invasion and metastasis. However, its effect on tumor-promoting macrophages and tumor suppressor macrophages in breast cancer progression remains unknown. In this study, we investigated the effects of Tau on macrophage polarization and its role in TNBC cell growth, invasion, and metastasis. We induced human THP-1 monocytes to differentiate into M2 macrophages through exogenous addition of interleukin-4. We used the TNBC cell lines MDA-MB-231 and BT-549 cultured in a conditioned medium from M2 macrophages to investigate the effect of Tau on tumor growth and invasion. We analyzed macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression by quantitative polymerase chain reaction. We also detected the PTEN-PI3K/Akt/mTOR signaling pathway that mediates M1 macrophage to suppress tumor invasion using western blotting. Our results showed that Tau inhibits breast cancer metastasis to the lungs in vivo and cell invasion by altering the polarization of tumor-associated macrophage in vitro. In addition, Tau can up-regulate PTEN expression, suppress the PI3K-Akt signaling pathway, and promote the M1 polarization of macrophages, which ultimately inhibits the metastasis of TNBC cells. Our findings suggest that Tau inhibits the activation of the PI3K-Akt-mTOR signaling pathway by up-regulating PTEN, promotes the proportion of M1 macrophages in tumor-associated macrophage, and suppresses the invasion and metastasis of TNBC. This provides a potential therapeutic approach to influence cancer progression and metastasis.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.1097/CJI.0000000000000515
Xuemeng Li, Fang Yang, Baogang Liu, Leiguang Ye, Jingwen Du, Xiaona Fan, Yue Yu, Mengwei Li, Li Bu, Zhuoqi Zhang, Lili Xie, Wuquan Li, Jiaqing Qi
SUMMARY Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P= 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P= 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P=0.048) was associated with a higher risk of CIP.
{"title":"Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.","authors":"Xuemeng Li, Fang Yang, Baogang Liu, Leiguang Ye, Jingwen Du, Xiaona Fan, Yue Yu, Mengwei Li, Li Bu, Zhuoqi Zhang, Lili Xie, Wuquan Li, Jiaqing Qi","doi":"10.1097/CJI.0000000000000515","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000515","url":null,"abstract":"SUMMARY\u0000Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P= 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P= 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P=0.048) was associated with a higher risk of CIP.","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140700753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}