Tumor-infiltrating CD8+ T cell is prognostic and predicts adjuvant chemotherapy benefit in patients with limited-stage small cell esophageal carcinoma.
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SUBMITTER: Zhang Z
PROVIDER: S-EPMC8236121 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCD103+CD8+ tissue-resident memory T (TRM) cells, associated with better overall survival among various malignancies, are thought to activate anti-tumour immune response and affect therapeutic sensitivity including both immunotherapy and adjuvant chemotherapy (ACT).MethodsTotally 650 muscle-invasive bladder cancer (MIBC) patients from three independent cohorts were included in this study for survival and cisplatin-based ACT response analysis. Another public data set consisting of 195 patients from IMvigor210 trial receiving PD-L1 blockade were involved in the assessment of immunotherapeutic response. Fifty-nine fresh tumour tissues were used to evaluate immune infiltration of CD103+CD8+ TRM cells.ResultsPatients with high CD103+CD8+ TRM cells infiltration, but not CD8+ T cells, are more likely to benefit from immunotherapy and ACT. The presence of TRM cells is highly associated with an enhanced IFNγ-enriched and T cell-inflamed anti-tumour microenvironment. Elevated CD103+CD8+ TRM cells infiltration correlated with superior ACT response in mismatch repair (MMR), homologous recombination (HR), PIK3CA/AKT and RAS/RAF pathway proficient or histone modification and cell cycle pathway deficient patients.ConclusionsCD103+CD8+ TRM cells played a crucial role in anti-tumour immunity and served as an ideal prognostic biomarker. It could be treated as a superior companion predictor for treatment response to PD-L1 inhibitor and ACT within MIBC patients.
| S-EPMC9130137 | biostudies-literature
Project description:Colorectal cancer (CRC) is one of the most common malignances worldwide. Chemoresistance remains a major issue in the field of CRC treatment. The present study aimed to investigate the potential role of polo-like kinase 2 (Plk2) in chemoresistance in CRC. The associations between Plk2 and clinicopathological factors, as well as chemotherapeutic benefit were analyzed with a publicly available CRC dataset. The correlation between Plk2 expression and chemosensitivity was further confirmed in CRC cells. Moreover, knockdown and exogenous overexpression experiments of Plk2 were carried out to uncover the potential role of Plk2 in regulating the chemoresistance of CRC cells. We found that the expression of Plk2 was significantly associated with proximally located tumors. In addition, it was found that high expression ofPlk2 was associated with deficient mismatch repair status, B‑raf serine/threonine kinase proto‑oncogeneand Kirsten rat sarcoma viral oncogene homolog mutations. By contrast, tumor protein 53 mutation was correlated with a low expression level of Plk2. A higher expression level of Plk2 significantly predicted a poorer outcome in patients with CRC. However, the prognostic significance was only observed in patients who received adjuvant chemotherapy. In CRC cells, higher levels of Plk2 were associated with increased resistance to chemotherapeutic agents. Knocking down the expression of Plk2 resulted in elevated cellular apoptosis induced by oxaliplatin. By contrast, exogenous overexpression of Plk2 exerted an anti-apoptotic effect and enhanced the resistance of CRC cells to chemotherapeutic agents. In conclusion, a high expression of Plk2 was associated with chemoresistant traits of CRC through inhibiting apoptosis. These results suggested that Plk2 may serve as a predictive marker for chemoresistance and a novel target in CRC treatment.
| S-EPMC5873899 | biostudies-literature
Project description:BackgroundTumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs).MethodsUsing a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining.ResultsCompared with CD8+ TIL-negative cases (n = 196, 48.6%), CD8+ TIL-positive cases (n = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p<0.001; multivariate HR: 0.372; 95% confidence interval (CI): 0.239-0.579, p<0.001]. In contrast, compared with CD68+ TAM-negative cases (n = 217, 54.1%), CD68+ TAM-positive cases (n = 184, 45.9%) had significantly poor RFS [log-rank p<0.001; multivariate HR: 2.182; 95% CI: 1.435-3.318, p<0.001]. Thus, patients with a positive CD8+ TIL and negative CD68+ TAM status exhibited significantly increased RFS. Multivariate analysis demonstrated that CD8+ TILs and CD68+ TAMs may serve as independent prognostic markers for RFS. Incorporating CD8+ TIL and CD68+ TAM statuses into the AJCC TNM system generated a predictive model with better predictive accuracy for RFS. More importantly, patients with a positive TIL and negative TAM status showed a tendency of improved RFS after postoperative adjuvant chemotherapy (PAC). Similar results were obtained by overall survival (OS) analysis.ConclusionsCD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC.Trial registrationThe current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481 ) on December 30, 2014.
| S-EPMC6744628 | biostudies-literature
Project description:Growing evidence shows tumor-infiltrating neutrophils (TINs) involvement in tumorigenesis. The objective of this study is to assess the prognostic effect of TINs and its impact on adjuvant chemotherapy benefits in muscle invasive bladder cancer (MIBC). A total of 142 MIBC patients from Zhongshan Hospital, 119 MIBC patients from FUSCC, and 405 MIBC patients from TCGA cohort were enrolled in the study. TINs were evaluated by immunohistochemical staining of CD66b or the CIBERSORT method. Patients with high TINs had a significantly poorer overall survival (p = 0.001, p < 0.001, and p = 0.002, respectively) in the three sets. In the multivariate analysis, the presence of high TINs (HR = 2.122, p = 0.007; HR = 3.807, p < 0.001; HR = 2.104, p = 0.001; respectively) was identified as an independent prognostic factor for overall survival in the three sets. More importantly, Low TINs patients had significantly longer overall survival in patients without ACT in the three sets. Gene set enrichment analysis showed that lymphocyte activation (p < 0.001) and T cell activation (p = 0.008) were significantly enriched in the low TINs group. In addition, TINs were negatively correlated with CD8+ T cells, suggesting that the status of high-TINs was linked to the status of immunosuppression in MIBC. TINs could be used as independent prognostic factor. Low TINs identified a subgroup of MIBC patients who appeared to benefit from adjuvant chemotherapy. Incorporation of TINs into TNM system could further stratify patients with different prognosis.
| S-EPMC5414863 | biostudies-literature
Project description:It is well accepted that the innate response is a necessary prerequisite to the formation of the adaptive response. This is true for T cell responses against infections or adjuvanted subunit vaccination. However, specific innate parameters with predictive value for the magnitude of an adjuvant-elicited T cell response have yet to be identified. We previously reported how T cell responses induced by subunit vaccination were dependent on the cytokine IL-27. These findings were unexpected, given that T cell responses to an infection typically increase in the absence of IL-27. Using a novel IL-27p28-eGFP reporter mouse, we now show that the degree to which an adjuvant induces IL-27p28 production from dendritic cells and monocytes directly predicts the magnitude of the T cell response elicited. To our knowledge, these data are the first to identify a concrete innate correlate of vaccine-elicited cellular immunity, and they have significant practical and mechanistic implications for subunit vaccine biology.
| S-EPMC5771264 | biostudies-literature
Project description:BackgroundSmall cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy-with or without immune checkpoint inhibitors (anti-PDs)-is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood.MethodsWe systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts-including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients' responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density.ResultsWe observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75-9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy.ConclusionsOur results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.
| S-EPMC8607595 | biostudies-literature
Project description:Tumor necrosis factor (TNF) family members participate in the body's antitumor immunity response and influence tumor prognosis and treatment response. However, little is known about the roles of TNF family members in small cell lung cancer (SCLC). Therefore, we conducted the first comprehensive investigation of TNF family members in patients with SCLC, with the goal of using them to predict prognosis and chemotherapy benefit. Abnormal genetic alterations and expression of TNF family members were found to be widespread in SCLC patients. Using LASSO Cox regression analysis, we constructed a TNF family-based signature that separated SCLC patients in the training set (n=77) into high- and low-risk groups with distinct survival and chemotherapy benefit, and the signature was well-validated in the validation set (n=137) by RT-qPCR. Importantly, the signature exhibited superior predictive performance and was identified as a novel independent prognostic factor. Additionally, different immune phenotypes were found between the low-risk and high-risk groups, and high-risk patients had higher CMTM6 expression, suggesting that these patients could benefit from therapeutic methods targeting CMTM6. We constructed the first clinically applicable TNF family-based signature for predicting prognosis and chemotherapy benefit for patients with SCLC. The findings reported here provide a new method for predicting the prognosis of SCLC patients and optimizing clinical management.
| S-EPMC8637339 | biostudies-literature
Project description:BackgroundAlthough PD-1 has been reported to be a marker of T-cell exhaustion in several malignancies, the biological role of PD-1+CD8+ T cells in gastric cancer (GC) remains unclear. Herein, we aimed to investigate the role of PD-1+CD8+ T cells in the tumour microenvironment and its clinical significance in GC.DesignsThis study included 441 tumour microarray specimens and 60 Flow cytometry specimens of GC patients from Zhongshan Hospital, and 250 GC patients from the Asian Cancer Research Group.ResultsHere, we demonstrated that PD-1+CD8+ T cells functioned as an independent adverse prognosticator in GC. In addition, an abundance of intratumoral PD-1+CD8+ T cells indicated worse chemotherapeutic responsiveness to fluorouracil in Stage III GC patients. Mechanistically, PD-1+CD8+ T cell high infiltration indicated an exhausted phenotype of global CD8+ T cells in GC tissues, which was characterised by elevated immune checkpoint expression including CTLA-4 and TIM-3, whereas decreased expression of perforin. Furthermore, PD-1+CD8+ T cell high-infiltration patients with Stage III GC held elevated activity of several therapeutic signal pathways.ConclusionsOur study highlighted that PD-1+CD8+ T cell abundance predicts inferior prognosis in GC, and may serve as a novel predictive biomarker to guide therapeutic option.
| S-EPMC9596411 | biostudies-literature
Project description:BackgroundThis study aimed to explore the potentially predictive role and dynamic changes of immune checkpoints on T cell subsets in patients with breast cancer receiving neoadjuvant chemotherapies.MethodsFluorescent multiplex immunohistochemistry (mIHC) was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in paired breast cancer samples before and after neoadjuvant therapies (NAT) in a prospective cohort (n = 50). Singleplex IHC was conducted to stain for CD3 in 100 cases with inclusion of extra retrospective 50 cases. Cell levels were correlated with clinicopathological parameters and pathological complete response (pCR).ResultsIn pretreatment tumors, the percentages of infiltrating CD8+ , PD1+ , PD1+ CD8+ , and the ratio of PD1+ CD8+ /CD8+ cells, were higher in pCR than non-pCR patients in either the stromal or intratumoral area, but PD1+ CD4+ , TIM3+ CD4+ , TIM3+ CD8+ cells and CD4+ /CD8+ ratio was not. Multivariate analyses showed that the percentage of intratumoral CD8+ cells (OR, 1.712; 95% CI: 1.052-2.786; P = 0.030) and stromal PD1+ CD8+ /CD8+ ratio (OR, 1.109; 95% CI: 1.009-1.218; P = 0.032) were significantly associated with pCR. Dynamically, reduction in the percentages of PD1+ , CD8+ and PD1+ CD8+ cells after therapy strongly correlated with pCR. Notably, incremental percentages of PD1+ CD8+ cells, rather than TIM3+ CD8+ , were shown in tumors from non-pCR patients after NAT. CD3 staining confirmed the percentage of T cells were associated with pCR.ConclusionsPD1+ CD8+ rather than TIM3+ CD8+ cells are main predictive components within tumor-infiltrating T cells in NAT breast cancer patients. Dynamically incremental levels of PD1+ CD8+ cells occurred in non-pCR cases after NAT, suggesting the combination of chemotherapy with PD1 inhibition might benefit these patients.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: PD1+ CD8+ , rather than TIM3+ CD8+ , T cells are the main component to predict the response of neoadjuvant therapies in breast cancer.What this study addsIncremental levels of PD1+ CD8+ T cells in non-pCR post-NAT tumors suggest PD1 inhibition might benefit in the neoadjuvant setting.
| S-EPMC7529566 | biostudies-literature
Project description:Host immunity has an essential role in the clinical management of cancers. Therefore, it is advantageous to choose therapies that can promote tumor cell death and concurrently boost host immunity. The dynamic tumor microenvironment (TME) determines whether an antineoplastic drug will elicit favorable or disparaging immune responses from tumor-infiltrating lymphocytes (TILs). CD8+ T cells are one of the primary tumor-infiltrating immune cells that deliver antitumor responses. Here, we review the influence of various factors in the TME on CD8+ T cell exhaustion and survival, and possible strategies for restoring CD8+ T cell effector function through immunotherapy.
| S-EPMC8131230 | biostudies-literature