Hirsutella sinensis Inhibits Lewis Lung Cancer via Tumor Microenvironment Effector T Cells in Mice

2018 ◽  
Vol 46 (04) ◽  
pp. 911-922 ◽  
Author(s):  
Huiying Fu ◽  
Lu Jin ◽  
Xia Shao ◽  
Yuanyuan Li ◽  
Fangming Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Suppressor Cell ◽  
Cordyceps Sinensis ◽  
Lewis Lung ◽  
Survival Times ◽  
Lewis Lung Cancer

Hirsutella sinensis fungus (HSF) is an artificial substitute of the well-known medicine Cordyceps sinensis with similar beneficial effects in humans. We previously found that HSF can regulate immune function and inhibit tumor growth; however, the mechanisms involved in these effects were still unclear. Accordingly, in this study, we investigated the effects of HSF on immune cell subsets in the tumor microenvironment in mice. The results showed that HSF inhibited Lewis lung cancer growth, alleviated abnormalities in routine blood tests, and enhanced tumor-infiltrating T cells, particularly the proportion of effector CD8[Formula: see text] T cells. In addition, HSF also ameliorated the immune-suppressive microenvironment and decreased the proportions of regulatory T cell and myeloid-derived suppressor cell populations. To confirm the effects of HSF on promotion of effector CD8[Formula: see text] T-cell production, we further evaluated changes in postoperative metastasis following treatment with HSF. Indeed, orthotopic lung metastasis was significantly suppressed, and survival times were increased in HSF-treated mice. Taken together, our findings suggested that HSF inhibited Lewis lung cancer by enhancing the population of effective CD8[Formula: see text] T cells.

The correlation between tumor microenvironment and the clonality of the T-cell repertoire in lung cancer and colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14524-e14524
Author(s):  
Hua Cao ◽  
Jingxian Duan ◽  
Shunda Jiang ◽  
Tianhao Mu ◽  
Ruilian Xu
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Clonal Expansion ◽  
T Helper ◽  
T Cell Clonality ◽  
Cell Clonality ◽  
Cell Clonal Expansion

e14524 Background: The tumor microenvironment has been shown to affect the responsiveness of immunotherapy. Effective anti-tumor immune response requires the activation and expansion of specific antigen-reactive T cell clones. It was reported that increased T cell clonality was associated with improved response to immunotherapy. However, what type of tumor microenvironment facilitates T cell clonal expansion remained controversial. The study aims to investigate the correlation between tumor microenvironment and the clonality of the T cell repertoire in lung cancer and colorectal cancer. Methods: 4 lung cancer patients and 4 colorectal cancer patients were enrolled in this study. Tumor tissues and peripheral blood samples were collected for RNA sequencing and T cell receptor CDR3 sequencing. The infiltration levels of 28 immune cells were estimated based on the mRNA expression of the genetic markers. The T cell clonality was defined as 1-Peilou’s evenness. Data were presented as mean± S.E.M. Results: The mean T cell clone counts in the blood samples of the 8 patients were 25676±4782 (ranging from 10259 to 45016), and the mean clonality of the TCR repertoires was 0.20±0.02 (ranging from 0.11 to 0.27). The clonality of T cells in colorectal cancer patients was similar to that of the lung cancer patients (0.22±0.02 versus 0.18±0.03, p = 0.31), showing comparable potentials of antigenic responses. The tumor infiltration of regulatory T cells, type 17 T helper cells, CD56bright natural killer cells, and natural killer cells varied greatly among patients, the coefficient of variation of those cells were 54.61%, 54.61%, 54.43%, and 55.62% respectively. In contrast, the coefficient of variation of monocytes was 23.34%, displaying a relatively even distribution among patients. The Pearson’s correlation coefficient was calculated to show the correlation between T cell clonality and the infiltration level of all 28 types of immune cells. Notably, only the infiltration of type 17 T helper cells significantly associated with T cell clonality, the positive correlation gave an R square value of 0.68 (r = 0.82, 95% confidence interval of 0.04-0.98, p = 0.04). The infiltration levels of CD4+ T cells, CD8+ T cells, regulatory T cells, type 1 and type 2 T cells, and gamma delta T cells were not affected by T cell clonal expansion. The expression of B cells, dendritic cells, macrophages, natural killer cells, and monocytes did not correlate with T cell clonal expansion. However, the abundance of neutrophils appears to positively correlate with T cell clonality (p = 0.09). Conclusions: The clonal expansion was significantly associated with the infiltration of type 17 T helper cells but not other subtypes of T cells, showing that the type 17 T helper cells are crucial to the antigenic responses in lung cancer and colorectal cancer. A neutrophil enriched tumor microenvironment may facilitate T cell clonal expansion.

scholarly journals Xiao-Ai-Ping, a TCM Injection, Enhances the Antigrowth Effects of Cisplatin on Lewis Lung Cancer Cells through Promoting the Infiltration and Function of CD8+T Lymphocytes

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Wanshuai Li ◽  
Yang Yang ◽  
Zijun Ouyang ◽  
Qi Zhang ◽  
Lu Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Lewis Lung ◽  
Lewis Lung Cancer ◽  
Antitumor Effects ◽  
Concentration Dependent Manner ◽  
And Function

Objectives. To investigate how Xiao-Ai-Ping injection, a traditional Chinese medicine and an ancillary drug in tumor treatment, enhances the antitumor effects of cisplatin on Lewis lung cancer (LLC) cells.Methods. LLC-bearing mice were daily intraperitoneally injected with various doses of cisplatin, Xiao-Ai-Ping, or cisplatin plus Xiao-Ai-Ping, respectively. Body weight and tumor volumes were measured every three days.Results. Combination of Xiao-Ai-Ping and cisplatin yielded significantly better antigrowth and proapoptotic effects on LLC xenografts than sole drug treatment did. In addition, we found that Xiao-Ai-Ping triggered the infiltration of CD8+T cells, a group of cytotoxic T cells, to LLC xenografts. Furthermore, the mRNA levels of interferon-γ(ifn-γ), perforin-1 (prf-1), and granzyme B (gzmb) in CD8+T cells were significantly increased after combination treatment of Xiao-Ai-Ping and cisplatin.In vitrostudies showed that Xiao-Ai-Ping markedly upregulated the mRNA levels ofifn-γ,prf-1,andgzmbin CD8+T cells in a concentration-dependent manner, suggesting that Xiao-Ai-Ping augments the function of CD8+T cells.Conclusions. Xiao-Ai-Ping promotes the infiltration and function of CD8+T cells and thus enhances the antigrowth effects of cisplatin on LLC xenografts, which provides new evidence for the combination of Xiao-Ai-Ping and cisplatin in clinic in China.

Effect of STING agonist on tumor immune microenvironment of non-inflamed lung cancer and efficacy of immune checkpoint blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 178-178
Author(s):  
Hongjae Chon
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Lung Carcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Anti Cancer

178 Background: Cancer immunotherapy targeting immune checkpoints are now emerging as a promising therapeutic strategy in various tumors. However, the treatment of T cell non-inflamed tumor which lacks intratumoral T cell infiltrates are still major clinical hurdle. Therefore, drugs that target signaling pathways to increase T cell infiltration in non-inflamed tumor microenvironment (TME) should be investigated. In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. Mice were injected with Lewis lung carcinoma cells on the right flank. STING agonist (cGAMP) was injected intratumorally. CD8+ and CD31+ cells were detected using immunofluorescence (IF) staining. Gene expressions of tumor microenvironment were analyzed by NanoString RNA sequencing. Flow cytometry (FACS) was performed to detect CD8+, CD4+, Treg and myeloid cell population. Tumor growths were evaluated in combination with anti-PD1 and STING agonist treatment. Results: Local injection of STING agonist effectively delayed tumor growth of LLC. STING agonist increased intratumoral CD8+ T cells and vascular disruption. Expressions of inhibitory checkpoint molecules (PD-1, PD-L1), cytokines (IFN), CD8+ and CD4+ T cells were increased, which showed that anti-cancer immune responses were augmented. Combination treatment of anti-PD-1 antibody and STING agonist synergistically decreased tumor growth. Conclusions: In this study, STING agonist was shown to delay tumor growth and remodel tumor microenvironment in non-inflamed lung carcinoma model. Combination therapy of STING agonist and immune checkpoint inhibitors (ICI) targeting PD-1 synergistically suppressed the growth of lung cancer which is resistant to ICI monotherapy. Collectively, our findings demonstrated that localized STING therapy effectively sensitizes non-inflamed lung cancer to systemic ICI treatment and induces a maximal anti-cancer immune response.

scholarly journals TMIC-49. ABROGATING CD70 EXPRESSION IN GBM RESULTS IN A REDUCED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi258-vi258
Author(s):  
Haipeng Tao ◽  
Linchun Jin ◽  
Hector Mendez-Gomez ◽  
Yu Long ◽  
Meng Na ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Critical Role ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Tumor Mouse Model ◽  
Immunosuppressive Microenvironment

Abstract BACKGROUND We found that CD70, as an immune modulator, in GBM plays a critical role in immunosuppression and tumor progression. Although CD70+ tumors recruit more CD3+ T cells than CD70— tumors do in patients with GBM, CD70 on GBM is also found to be involved in promoting CD8+ T cell death. The experiments by overexpressing or silencing CD70 in a primary tumor demonstrate that it can alter cell growth, survival, migration, and morphology of GBM cells. CD70 is negatively correlated with survival in patients with gliomas. These results suggest that CD70 is involved in immunosuppression in GBM. OBJECTIVE To determine if abrogating CD70 in tumor using CD70CAR-T cells could reverse the immunosuppressive microenvironment and enhance overall endogenous tumor immunity against both CD70+ and CD70— tumors, which might help to overcome a key obstacle— tumor-heterogeneity using single-targeted CAR-T cell therapy. METHODS CD70 was overexpressed (~75% positivity) in KR158 GBM line. Murine CD70CAR T cells were used to eliminate CD70+ tumors in an immunocompetent orthotopic tumor mouse model. Tumor-bearing mice were administered the CD70CAR T and vector-tranduced T cells, followed by IVIS imaging for tumor growth. The presentation and phenotype of CAR T cells and endogenous immune cell populations in tumors and spleens were measured. RESULTS Five weeks post treatment, CD4+ T cells were found to be the dominant T cell population in tumors for both CAR-T and endogenous T cells. While the CAR-T cells shrank the tumors, fewer PD-1 expressing endogenous T cells, as well as granulocytic MDSC, but not monocytic MDSC were observed in the tumor (not in spleen) for the CAR-T group, compared to the vector group. No significant changes were seen for NK cells and Tregs between the groups. CONCLUSION This study suggests that eliminating CD70+ tumor cells may reverse the immunosuppressive landscape of the tumor microenvironment.

scholarly journals The evolution of T-cell receptor repertoire in different stages of non-small cell lung cancer

2020 ◽  
Author(s):  
Ziqi Jia ◽  
Yadong Wang ◽  
Xiaoying Yang ◽  
Pancheng Wu ◽  
Yanyu Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Background The intricate relationship between the tumor and host was not well understood, and antigen-specific T cell is fundamental in understanding the interaction. TCR repertoire analysis which described TCR clonotypes and TCR numbers has shown that TCRs with high frequency was tumor-specific T cells, while others might be ‘bystander’ T cells within tumors. However, how these “expanded” tumor-specific T cells was selected during the tumor development was not clear. Methods We retrospectively analyzed TCR sequencing and mutation sequencing results from 144 non-small cell lung cancer (NSCLC) patients. Results A rich TCR repertoire comprising thousands of different TCR sequences was identified in all stages of NSCLC, with most TCR clonotypes presented at low frequency. Interestingly, Stage IV NSCLC tumors contain more expanded TCRs as compared to earlier stages, however, lymph node metastasis or tumor size had little impact on expanded TCRs. Moreover, accumulation of mutations did not significantly change the number of TCR clonotypes, however, EGFR mutant patients had significantly lower while KRAS mutant patients had significantly higher number of TCR clonotypes especially in terms of those “expanded” TCRs. Conclusions In summary, T cells in the tumor microenvironment were gradually activated with tumor development. Critical events such as distal metastases and generation of EGFR or KRAS mutations might be the major factors affecting the changing of tumor-specific T cells in the tumor microenvironment.

scholarly journals miR-21 regulates immunosuppression mediated by myeloid-derived suppressor cells by impairing RUNX1-YAP interaction in lung cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Guangping Meng ◽  
Jinying Wei ◽  
Yanjun Wang ◽  
Danhua Qu ◽  
Jie Zhang
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Suppressor Cells ◽  
Mouse Serum ◽  
Myeloid Derived Suppressor Cells ◽  
Lewis Lung ◽  
Lewis Lung Cancer ◽  
Gm Csf ◽  
Flow Cytometric ◽  
Tumor Tissues

Abstract Background Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity and contribute to immunosuppressive microenvironment during tumor development including lung cancer. Accumulating evidence shows microRNAs (miRNAs) affect tumor-expanded MDSC accumulation and function in tumor microenvironment and favor solid tumor growth. Herein, we aim to characterize the role of miR-21 in regulating the accumulation and activity of MDSCs in lung cancer. Methods The proportions of MDSCs, T helper cells (Th), and cytotoxic T lymphocytes (CTL) were evaluated by flow cytometric analyses of peripheral blood and tumor tissues collected from Lewis lung-cancer-bearing mice. T cell proliferation assay was performed in CD4+ or CD8+ T cells cocultured with MDSCs. MDSC apoptosis was examined by flow cytometric analysis. The levels of IL-10, TGF-β, and GM-CSF in mouse serum were determined by ELISA. miR-21 targeting RUNX1 and RUNX1 interaction with YAP were evaluated by RIP, dual-luciferase reporter gene, and ChIP assays. Results MiR-21 inhibition by its antagomir reduced the proportion of MDSCs, increased the proportion of Th and CTL in peripheral blood and tumor tissues of Lewis lung-cancer-bearing mice, protected Th and CTL from the suppression of MDSCs, increased apoptosis of MDSCs, but reduced IL-10, TGF-β and GM-CSF levels in mouse serum. RUNX1 could transcriptionally inhibit the YAP expression, whereas miR-21 targeting RUNX1 led to elevated YAP expression levels. Mechanistic investigation showed that miR-21 maintained MDSC accumulation in tumor microenvironment and promoted immunosuppressive ability of MDSCs in Lewis lung-cancer-bearing mice by down-regulating RUNX1and up-regulating YAP. Conclusions Taken together, the study provides evidence that targeting miR-21 in MDSCs may be developed as an immunotherapeutic approach to combat lung cancer development.

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