Tumor-Infiltrating CD8+ T Cells Driven by the Immune Checkpoint-Associated Gene IDO1 Are Associated With Cervical Cancer Prognosis
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SUBMITTER: Zhang S
PROVIDER: S-EPMC8578845 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundsThe high morbidity and mortality of lung cancer are serious public health problems. The prognosis of lung cancer and whether to apply immune checkpoint blockade (ICB) are currently urgent problems to be solved.MethodsUsing R software, we performed Kaplan-Meier (K-M) analysis, Cox regression analysis, functional enrichment analysis, Spearman correlation analysis, and the single-sample gene set enrichment analysis.ResultsOn the Tumor IMmune Estimation Resource (TIMER2.0) website, we calculated the abundance of tumor-infiltrating immune cells (TIICs) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. B cell and myeloid dendritic cell (DC1) were independent prognostic factors for LUAD and LUSC patients, respectively. Enrichment analysis confirmed that genes highly related to B cell or DC1 were closely related to the immune activation of lung cancer patients. In terms of adaptive immune resistance markers, CD8A, CD8B, immunomodulators (immunostimulants, major histocompatibility complex, receptors, and chemokines), immune-related pathways, tumor microenvironment score, and TIICs, high B cell/DC1 infiltration tissue was inflamed and immune-activated and might benefit more from the ICB. Genes most related to B cell [CD19, toll-like receptor 10 (TLR10), and Fc receptor-like A (FCRLA)] and DC1 (ITGB2, LAPTM5, and SLC7A7) partially clarified the roles of B cell/DC1 in predicting ICB efficacy. Among the 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, there were three and four KEGG pathways, which partially explained the molecular mechanisms by which B cell and DC1 simultaneously predicted the prognosis and efficacy of immunotherapy, respectively. Among five immune subtypes, the abundance of B cell/DC1 and expression of six hub genes were higher in immune C2, C3, and C6.ConclusionB cell and DC1 could predict the prognosis and ICB efficacy of LUAD and LUSC patients, respectively. The six hub genes and seven KEGG pathways might be novel immunotherapy targets. Immune C2, C3, and C6 subtypes of lung cancer patients might benefit more from ICB therapy.
| S-EPMC8370893 | biostudies-literature
Project description:Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT. We tracked tumor antigen-specific CTL frequencies and phenotype before and after ICT in responding and non-responding animals. Tumor antigen-specific CTLs increased within tumor and draining lymph nodes after ICT, and exhibited an effector memory-like phenotype, expressing IL-7R (CD127), KLRG1, T-bet, and granzyme B. Responding tumors exhibited higher infiltration of effector memory tumor antigen-specific CTLs, but lower frequencies of regulatory T cells compared to non-responders. Tumor antigen-specific CTLs persisted in responding animals and formed memory responses against tumor antigens. Our results suggest that increased effector memory tumor antigen-specific CTLs, in the presence of reduced immunosuppression within tumors is part of a successful ICT response. Temporal and nuanced analysis of T cell subsets provides a potential new source of immune based biomarkers for response to ICT.
| S-EPMC7688517 | biostudies-literature
Project description:The present study aimed to explore the mechanism by which the immune landscape of the tumor microenvironment influences bladder cancer. CIBERSORT and ssGSEA analyses revealed that M2 macrophages accounted for the highest proportion from 22 subsets of tumor‑infiltrating immune cells and were enriched in higher histologic grade and higher pathologic stage bladder cancer and 'basal' subtype of muscle invasive bladder cancer (MIBC). Kaplan‑Meier survival curve analysis indicated that patients with high numbers of infiltrating M2 macrophages had worse overall and disease‑specific survival rates. RNA sequencing and immunohistochemistry results indicated that M2 macrophages were enriched in MIBC and promoted angiogenesis. M2 macrophage infiltration was higher in bladder cancer tissues with mutant TP53, RB transcriptional corepressor 1, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α, lysine methyltransferase 2A, lysine demethylase 6A and apolipoprotein B mRNA editing enzyme catalytic‑polypeptide‑like, but lower in tissues with mutant fibroblast growth factor receptor 3 (FGFR3), E74‑like ETS transcription factor 3, PC4 and SFRS1 interacting protein 1 and transmembrane and coiled‑coil domains 4. In addition, M2 macrophage infiltration was lower in the tissues with amplified FGFR3, erb‑b2 receptor tyrosine kinase 2, BCL2‑like 1, telomerase reverse transcriptase and tyrosine‑3‑monooxygenase/tryptophan‑5‑monooxygenase activation protein ζ, as well as in the tissues with deleted cyclin‑dependent kinase inhibitor 2A, CREB binding protein, AT‑rich interaction domain 1A, fragile histidine triad diadenosine triphosphatase, phosphodiesterase 4D, RAD51 paralog B, nuclear receptor corepressor 1 and protein tyrosine phosphatase receptor type D. Finally, seven micro (mi) RNAs (miR‑214‑5p, miR‑223‑3p, miR‑155‑5p, miR‑199a‑3p, miR‑199b‑3P, miR‑146b‑5p, miR‑142‑5p) which were expressed differentially in at least three mutant genes and were positively correlated with M2 macrophage infiltration as well as expressed highly in high grade bladder cancer were identified. Overall, the present study concluded that M2 macrophages are the predominant tumor‑infiltrating immune cell in bladder cancer and differentially expressed miRNAs due to cancer‑specific genomic alterations may be important drivers of M2 macrophage infiltration. These findings suggested that M2 macrophage infiltration may serve as a potential immunotherapy target in bladder cancer.
| S-EPMC6610042 | biostudies-literature
Project description:In a recent report, [Zhang et al. (2003) N. Engl. J. Med. 348, 203-213], the presence of CD3+ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18-0.60; P = 0.0003]. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16-0.55; P = 0.0001). These results indicate that CD4+ TILs influence the beneficial effects of CD8+ TIL. This unfavorable effect of CD4+ T cells on prognosis was found to be due to CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17-0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8+ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+ TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.
| S-EPMC1311741 | biostudies-literature
Project description:BackgroundTumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC).MethodsA CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score.ResultsThree CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts.ConclusionsThis study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.
| S-EPMC8458312 | biostudies-literature
Project description:Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells. To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460). Localization of CD103+ cells in the tumor was assessed by immunofluorescence. Furthermore, use of CD103 as a response biomarker was assessed in an in vivo E6/E7+ tumor model. Our results show that CD103 gene expression was strongly correlated with cytotoxic T cell markers (e.g. CD8/GZMB/PD1) in the TCGA series. In line with this, CD103+ cells in the IHC series co-expressed CD8 and were preferentially located in cervical tumor epithelium. High CD103+ cell infiltration was strongly associated with an improved prognosis in both series, and appeared to be a better predictor of outcome than CD8. Interestingly, the prognostic benefit of CD103 in both series seemed limited to patients receiving radiotherapy. In a preclinical mouse model, HPV E6/E7-targeted therapeutic vaccination in combination with radiotherapy increased the intratumoral number of CD103+ CD8+ T cells, providing a potential mechanistic basis for our results. In conclusion, CD103 is a promising marker for rapid assessment of tumor-reactive T cell infiltration of cervical cancers and a promising response biomarker for E6/E7-targeted immunotherapy.
| S-EPMC5599086 | biostudies-literature
Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1- TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
| S-EPMC6336113 | biostudies-literature
Project description:IntroductionTumor-infiltrating lymphocytes (TILs) have predictive and prognostic value in breast cancer (BC) and exert a protective function against tumor growth, indicating that it is susceptible to treatment using adoptive cell transfer of TILs or T cell receptor (TCR)-based therapies. TCR can be used to identify naturally tumor-reactive T cells, but little is known about the differences in the TCR repertoires of CD4+ and CD8+ TILs.MethodsTCR high-throughput sequencing was performed using TILs derived from the initial cultures of 11 BC biopsies and expanded and sorted CD4+ and CD8+ TILs as well as using PBMCs from healthy donors expanded and sorted using the same methodology.ResultsPhysicochemical TCR differences between T cell subsets were observed, as CD4+ TILs presented larger N(D)Nnt TRB sequences and with a higher usage of positively charged residues, although only the latest was also observed in peripheral T cells from healthy individuals. Moreover, in CD4+ TILs, a more restricted TCR repertoire with a higher abundance of similar sequences containing certain amino acid motifs was observed.DiscussionSome differences between CD4+ and CD8+ TCRs were intrinsic to T cell subsets as can also be observed in peripheral T cells from healthy individuals, while other were only found in TILs samples and therefore may be tumor-driven. Notably, the higher similarity among CD4+ TCRs suggests a higher TCR promiscuity in this subset.
| S-EPMC10436466 | biostudies-literature
Project description:Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8+ , CD20+ and CD204+ cells in tumor islets, and for CD8+ , CD20+ and FOXP3+ cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.
| S-EPMC7293080 | 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