Tumor-infiltrating Immune Cell Landscape Research Articles

Gene Expression Profiles Infer — The Landscape of Tumor-Infiltrating Immune Cells in Ovarian Cancer and their Clinical Significance

Gene Expression Profiles Infer — The Landscape of Tumor-Infiltrating Immune Cells in Ovarian Cancer and their Clinical Significance

G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth.

Melanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear. We established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR. GPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity. GPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.

Multi-omics profiling identifies C1QA/B+ macrophages with multiple immune checkpoints associated with esophageal squamous cell carcinoma (ESCC) liver metastasis

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignant tumor lacking effective treatments; 20% of ESCC patients develop liver metastasis with an extremely short survival time of ≈5 months. The tumor microenvironment (TME) plays a crucial role in tumor homeostasis, but the relationship between the ESCC TME and liver metastasis is still unknown. To identify potential cell populations contributing to ESCC liver metastasis, single-cell RNA (scRNA) sequencing data were analyzed to identify the major cell populations within the TME. Each of the major cell populations was re-clustered to define detailed cell subsets. Thereafter, the gene set variation analysis (GSVA) score was calculated for the bulk RNA-seq data based on the gene signatures of each cell subset. The relationship between the GSVA score of each cellular subset and clinical outcome was further analyzed to identify the cellular subset associated with ESCC liver metastasis, which was validated by multiplex immunohistochemistry. C1QA/B+ tumor-associated macrophages (TAMs) acted as the central regulator of the ESCC TME, closely associated with several key cell subsets. Several immune checkpoints, including CD40, CD47 and LGALS9, were all positively expressed in C1QA/B+ macrophages, which may exert central regulatory control of immune evasion by ESCC via these immune checkpoints expressions. Our results comprehensively revealed the landscape of tumor-infiltrating immune cells associated with ESCC prognosis and metastasis, and suggest a novel strategy for developing immunotherapies for ESCC liver metastasis by targeting C1QA/B+ TAMs.

The Landscape of Tumor-Infiltrating Immune Cells in Feline Mammary Carcinoma: Pathological and Clinical Implications.

Feline mammary carcinoma (FMC) shares key molecular and clinicopathological features with human breast cancer. We have herein studied the inflammatory infiltrate of FMC in order to uncover potential therapeutic targets and prognostic markers. To this end, the expression of different markers (CD3, CD4, CD8, CD20, CD56, FoxP3, CD68 and CD163) was analyzed in total, stromal (s) and intratumoral (i) tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), in 73 feline mammary carcinomas. The results revealed that higher percentages of sCD8+ TILs were associated with longer disease-free survival (p = 0.05) and overall survival (p = 0.021). Additionally, higher percentages of iCD4+ TILs correlated with positive lymph node status (p = 0.003), whereas CD163+ TAMs were associated with undifferentiated tumors (p = 0.013). In addition, sCD3+ (p = 0.033), sCD8+ (p = 0.044) and sCD68+ (p = 0.023) immune cells were enriched in triple negative normal-like carcinomas compared to other subtypes. Altogether, our results suggest that specific subsets of immune cells may play a major role in clinical outcome of cats with mammary carcinoma, resembling what has been reported in human breast cancer. These data further support the relevance of the feline model in breast cancer studies.

Identification of a Competing Endogenous RNA Network Related to Immune Signature in Lung Adenocarcinoma.

BackgroundThe establishment of immunotherapy has led to a new era in oncotherapy. But the signature of immune-related genes (IRGs) in LUAD remains to be elucidated. Here we use integrated analysis to identify IRGs roles in immune signature and detect their relationship with competing endogenous RNA (ceRNA) networks in LUAD progression.MethodsBy analyzing the RNA-seq data from different platforms, we recognized the differentially expressed genes (DEGs) of each platform and screened out the top 20 hub IRGs related to immune responses. Then, we applied the CIBERSORT algorithm to explore the landscape of tumor-infiltrating immune cells (TILs) in LUAD and their connection with hub genes. Next, we predicted and validated the upstream miRNAs and lncRNAs according to their expression and prognostic roles. Finally, we constructed and validated an immune-related ceRNA network by co-expression analysis.ResultsA total of 71 IRGs were identified among 248 DEGs, which play key roles in immune responses. CIBERSORT analysis showed that six hub genes were closely related to TILs, such as SPP1 and naive B cells (R = −0.17), TEK and resting mast cells (R = 0.37). Stepwise prediction and validation from mRNA to lncRNA, including 6 hub genes, 5 miRNAs, and 9 lncRNAs, were applied to construct a ceRNA network. Ultimately, we confirmed the TMPO-AS1/miR-126-5p/SPP1 and CARD8-AS1/miR-21-5p/TEK as immune-related ceRNA networks in LUAD progression.ConclusionWe elucidated two immune-related ceRNA networks in LUAD progression, which can be considered as immunotherapy targets for this disease.

The prognostic landscape of tumor-infiltrating immune cells in lung squamous cell carcinoma.

BackgroundExploring novel biomarkers and developing effective therapeutic strategies can improve the prognosis of lung squamous cell carcinoma (LUSC) in the future. The prognostic value of tumor-infiltrating immune cells (TICs) in solid tumors has been extensively studied. However, the landscape of TICs involved in the prognosis of non-small cell lung cancer (NSCLC), especially in LUSC, remains unclear and should be systematically investigated.MethodsThis retrospective study analyzed the immune-related transcriptional profiles of 490 LUSC patients from The Cancer Genome Atlas (TCGA) cohort. Using the CIBERSORT method, TICs were evaluated and examined for their association with overall survival (OS) in LUSC.ResultsOut of the 27 TICs, 14 were correlated with prognosis in LUSC. A novel prognostic model characterized by fewer memory B cells and more central memory CD8 T cells, regulatory T cells (Tregs), and plasmacytoid dendritic cell (pDC) infiltration predicted poor OS in LUSC with high accuracy. The 1-, 3-, and 5-year areas under the curve (AUC) were 0.95, 0.98, and 0.96, respectively, in the training cohort. This finding was further validated in the validation cohort, where the 1-, 3-, and 5-year AUCs were 0.95, 0.98, and 0.95, respectively.ConclusionsThese findings may provide more effective prognostic biomarkers and potential therapeutic targets for the immunotherapy of LUSC.

Prognostic landscape of tumor-infiltrating immune cells and immune-related genes in the tumor microenvironment of gastric cancer.

The tumor microenvironment is closely related to the progression and immune escape of tumor cells. Tumor-infiltrating immune cells (TIICs) and immune-related genes (IRGs) are indispensable components of the tumor microenvironment and have been demonstrated to be highly valuable in determining the prognosis of multiple cancers. To elucidate the prognostic value of TIICs and IRGs in gastric cancer, we conducted a comprehensive analysis focusing on the abundances of 22 types of TIICs and differentially expressed IRGs based on a dataset from The Cancer Genome Atlas (TCGA). The results showed that great composition differences in TIICs and immune cell subfractions were associated with survival outcomes in different stages. Additionally, 29 hub genes were characterized from 345 differentially expressed IRGs and found to be significantly associated with survival outcomes. Then, an independent prognostic indicator based on ten IRGs was successfully constructed after multivariate adjustment for some clinical parameters. Further validation revealed that these hub IRGs could reflect the infiltration levels of immune cells. Thus, our results confirmed the clinical significance of TIICs and IRGs in gastric cancer and may establish a foundation for further exploring immune cell and gene targets for personalized treatment.

The prognostic landscape of tumor-infiltrating immune cells in cervical cancer

Tumor-infiltrating immune cells (TICs) are highly relevant to tumor development and are promising prognostic biomarkers. However, the precise assessment of TICs is limited by the deficiencies of traditional measurements, such as the lack of phenotypic markers. Here, we analyzed the composition of TICs in cervical cancer based on RNA expression data with a metagene approach called CIBERSORT and evaluated the prognostic value of TICs. The immune infiltration profiles functioned as intrinsic features to distinguish cervical cancer from normal tissue. According to the Cox regression analysis, higher levels of activated memory CD4+ T cells were independently associated with favorable overall survival (OS) (hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.57–0.89; p = 0.003), whereas a higher fraction of activated mast cells was independently associated with adverse outcomes (HR = 1.53, 95% CI: 1.23–1.91; p < 0.001). Furthermore, a novel prognostic model named aTMNs (activated memory CD4+ T cells, activated mast cells and activated natural killer [NK] cells) was constructed to predict OS in cervical cancer with high accuracy (area under the curve [AUC] = 0.723, concordance index [C-index] = 0.738): risk score = −0.34508 × (proportion of activated memory CD4+ T cells) + 0.426841 × (proportion of activated mast cells) + 0.272202 × (proportion of activated NK cells). The aTMNs model outperformed the immunomodulator model (AUC = 0.673, C-index = 0.693). Overall, TICs are important prognostic determinants in cervical cancer and may be a useful resource for the development of effective immunotherapy.

The Prognostic Landscape of Tumor-Infiltrating Immune Cells and Immune Checkpoints in Glioblastoma.

Tumor-infiltrating immune cells are part of a complex microenvironment and associated with improved clinical outcomes in a broad range of tumor types. However, a detailed map for the prognostic landscape of tumor-infiltrating immune cells and immune checkpoint modulators in glioblastoma is still lacking. Here, with the web-accessible resource, The Cancer Immunome Archive, 28 types of both adaptive and innate tumor-infiltrating immune cells were characterized in glioblastoma. Tumors lacking central memory CD4 T cells or natural killer cells were associated with better prognosis in glioblastoma, as verified by immunohistochemical analysis. Moreover, Kaplan-Meier analysis for a total of 71 key immune checkpoint molecules revealed that the expression level of inducible T cell costimulators, tumor necrosis factor superfamily member 14, and UL16 binding protein 1 were negatively correlated with the clinical outcome of patients with glioblastoma. In addition, there was a significant difference between nontumor and glioblastoma samples of several immune checkpoint modulators based on the expression level of their corresponding gene. Collectively, the annotation of tumor-infiltrating immune cells and immune checkpoint modulators in glioblastoma provides a valuable resource for identifying their involvement in tumor escape mechanisms and response to therapy.