Fertility preservation in BRCA mutation carriers-efficacy and safety issues: a review.

BRCA mutation carriers face various situations that influence their fertility potential. There is still a lack of guideline or expert consensus on Fertility Preservation (FP) in BRCA mutation carriers and the necessity and safety of FP in BRCA mutation carriers is still in dispute. This review aims to focus on the population of BRCA mutation carriers by analyzing the existing FP strategies, comprehensively comparing the pros and cons of each strategy and its applicability.FP is a suggestion for BRCA mutation carriers with birth planning. Different FP strategies have different characteristics. Considering the particularity of BRCA mutation carriers, multiple factors need to be carefully considered. This review focuses on the applicability of each FP method for carriers under various circumstances. Available FP strategies including oocyte cryopreservation, ovarian tissue cryopreservation, preimplantation genetic diagnosis, and egg/embryo donation are analyzed by comparing existing methods comprehensively. In the attempt to provide an up-to-date decision-making guidance. Conditions taking into consideration were the carrier's age, the risk of breast and ovarian metastasis, plans for oncotherapy, FP outcome, time available for FP intervention and accessibility.Overall, FP is necessary and safe for BRCA mutation carriers. Among all available FP methods, oocyte cryopreservation is the most reliable procedure; ovarian tissue cryopreservation is the only way for preserving both fertility and endocrine function, recommended for pre-pubertal carriers and when time is limited for oocyte stimulation. A clear framework provides frontline clinical practitioners a new thought and eventually benefit thousands of BRCA mutation carriers.

Decreased IFIT2 Expression Promotes Gastric Cancer Progression and Predicts Poor Prognosis of the Patients.

BACKGROUND/AIMS: The status of interferon (IFN) signaling pathway has been shown to be closely associated with the response of immune checkpoint blockade therapy against advanced human cancers. IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), also known as IFN-stimulated gene 54 (ISG54), is one of the most highly responsive ISGs, which can inhibit the proliferation and migration of cancer cells, and regulate viral replication, resulting in anti-cancer and anti-viral effects. In the present study, we aimed to investigate the role of IFIT2 in human gastric cancer. METHODS: Immunohistochemistry assay was used to investigate the correlation between the IFIT2 expression in cancer tissues and clinical parameters of gastric cancer patients. Knockdown of IFIT2 was performed using RNAi to assess the role of IFIT2 in the regulation of biological behaviors in human gastric cancer cell lines. RESULTS: IFIT2 expression in gastric cancer tissues was significantly associated with tumor stage and postoperative prognoses of the patients. Moreover, decreased IFIT2 expression in human gastric cancer cell lines SGC-7901 and AGS significantly increased the cell viability, cell migration and the ratios of cells in S phase. CONCLUSION: Our present study demonstrated that the decreased IFIT2 expression could promote the gastric cancer progression and predict poor therapeutic outcomes of the patients.

MicroRNA-203 Increases Cell Radiosensitivity via Directly Targeting Bmi-1 in Hepatocellular Carcinoma.

BACKGROUND: B-cell-specific moloney leukemia virus insertion site 1 (Bmi-1) plays important roles in various cancers, but its regulation through microRNAs (miRNAs) and its functions in hepatocellular carcinoma (HCC) remains unclear. METHODS: We evaluated the expression and prognostic significance of Bmi-1 in HCC by using tissue samples and The Cancer Genome Atlas (TCGA) data sets. The relationship between miRNAs and Bmi-1 was verified by bioinformatics prediction and immunofluorescence. Colony formation and apoptosis assays were used to reveal the effect of miR-203 on radiosensitivity. RESULTS: The Bmi-1 mRNA and protein were upregulated in HCC tissues. Cox regression multivariate analyses showed that Bmi-1 overexpression was an independent prognostic parameter for HCC patients. The expression level of Bmi-1 was negatively associated with miR-203 levels in HCC tissues. Dual-luciferase reporter assays showed that miR-203 could target the 3' untranslated region (3'-UTR) of Bmi-1 directly. Overexpression of miR-203 in HepG2 and Smmc-7721 cells increases their sensitivity to ionizing radiation in vitro and in vivo. Moreover, the improved cell radiosensitivity induced by miR-203 could be rescued by restoration of Bmi-1 expression. CONCLUSIONS: Bmi-1 could improve the predictive accuracy for HCC patients' survival. Moreover, miR-203 enhance cell radiosensitivity in vitro and in vivo by targeting Bmi-1 in HCC.

Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.

Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses.

The increase of circulating PD-L1-expressing CD68(+) macrophage in ovarian cancer.

Tumor-associated macrophages (TAMs) have been characterized as a critical population of immunosuppressive cells in a variety of tumor types. PD-L1 (also termed B7-H1) has been described to exert co-inhibitory and immune regulatory functions. Here, in ovarian cancer, PD-L1 is selectively overexpressed on some TAM compared that of benign ovarian disease. When expanding the data in peripheral blood, the proportion of PD-L1(+)CD68(+) cell among CD68(+) cells and the intensity of PD-L1 staining on CD68(+) cell in healthy group were similar to that observed in ovarian cyst group; instead, these two measures were significantly higher in ovarian cancer group, thereafter related to TNM stage. Interestingly, intracellular levels of IL-10, IL-6, TNF-α, and IFN-γ in PD-L1(+)CD68(+) macrophage were higher than those in PD-L1(-)CD68(+) macrophage, especially IL-6 expression. Based on the PD-L1 receptor PD-1 expression on tumor-infiltrating cytotoxic cells, our data supported that expression of PD-L1 on TAM promoted apoptosis of T cells via interaction with PD-1 on CD8(+)T cells. Taken together, these results suggested that PD-L1-expressing macrophage represents a novel suppressor cell population in ovarian cancer, which contributes immune escape of ovarian cancer.

The Clinical Significance of Abnormal Tim-3 Expression on NK Cells from Patients with Gastric Cancer.

AIM: To investigate the clinical significance of Tim-3 (T-cell immunoglobulin- and mucin-domain-containing molecule 3) expression in natural killer (NK) cells from patients with gastric cancer. MATERIALS AND METHODS: Sixty-two patients with gastric cancer and 32 healthy controls were recruited for this study. Tim-3 expression in peripheral blood samples was analyzed using flow cytometry. The expression pattern of Tim-3 on NK cells was also confirmed using a gastric cancer-bearing mouse model. To further investigate the mechanisms that regulate Tim-3 expression, T-bet(-/-), Eomes(-/-), and Eomes/T-bet double knockout mice were utilized. Additionally, we statistically analyzed the clinical significance of Tim-3 expression on NK cells. RESULTS: We found that the levels of Tim-3 in NK cells obtained from patients with gastric cancer were significantly higher than the levels in healthy controls. Clinical analyses showed that Tim-3 levels on NK cells were associated with advanced tumor stage. In a tumor-bearing mouse model, Tim-3 levels in NK cells increased with tumor growth, indicating that tumor progression could induce Tim-3 expression in NK cells. Finally, we report that T-bet is a key factor involved in regulating Tim-3 expression. CONCLUSION: Our data indicate that Tim-3 expression on NK cells is regulated by T-bet, and that Tim-3 levels correlate with advanced stages of gastric cancer.

CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

CD83 is commonly known as a specific marker for mature dendritic cells. It has been shown to be important for CD4(+) T-cell development in the thymus. However, its function in the peripheral immune system remains enigmatic. Here, we show that CD83 inhibits proliferation and production of IL-2 and IFN-γ by T cells, and the inhibitory effect of CD83 is mediated by monocytes. Prostaglandin E2 (PGE(2)), but not IL-10 or TGF-ß, was up-regulated specifically by CD83 in monocytes. Consistent with high levels of PGE(2), expression of COX-2 also was increased upon CD83 treatment. NF-κB activation also is required for induction of PGE(2) by CD83. Finally, application of the COX-2-selective inhibitor NS-398 fully prevented CD83-triggered inhibition of T-cell responses. Our study establishes an immune-regulatory mechanism by CD83 via stimulation of PGE(2) production in monocytes.

Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer.

In the present study, we studied the expression of T-bet, a key marker for type 1 immune responses, within the tumor microenvironment of gastric cancer, and analyzed its association with clinicopathological parameters. One hundred and fifty-two archival paraffin-embedded gastric tumor tissues were collected, and the expression of T-bet in these cancer tissue specimens was examined by immunohistochemistry. T-bet(+) tumor-infiltrating lymphocytes (TILs) in some gastric cancer tissues were further characterized by flow cytometric analysis. The density of T-bet(+) TILs in gastric cancer tissues in relation to patient's clinicopathological parameters and postoperative prognosis has been analyzed. Herein, we have found significant increases in T-bet(+) lymphocytes in tumor tissues as compared with normal stomach tissues, gastritis tissues or gastric polyp specimens. T-bet(+) cells mainly consisted of CD4(+), CD8(+) and CD56(+) TILs. In addition, lower numbers of T-bet(+) TILs were associated with poor clinicopathological parameters such as invasion to muscular layer, larger tumor size and advanced cancer stages. Moreover, patients with higher numbers of T-bet(+) TILs have longer disease-free survival and overall survival. Thus, our study supports the idea that tumor growth elicits spontaneous type 1 cellular immune responses and tumor progression is associated with suppression of antitumor immunity. T-bet expression within tumor can serve as a prognostic indicator for gastric cancer and a potential biomarker for immunotherapy.

CD40 signal regulates CXCR4 mediating ovarian carcinoma cell migration: implications for extrapelvic metastastic factors.

Ovarian carcinomas are highly invasive, especially in the peritoneal cavity. SDF-1α and its receptor, CXCR4, play a crucial role in migration of cancer cells. Here, SDF-1α directed HO8910 cell migration, but not SKOV3 cells. After being educated to express CXCR4 in vivo or by treating with sCD40L, SDF-1α reexhibited the ability of directing SKOV3 cell migration, which could be antagonized by CXCR4-neutralizing antibody. Furthermore, concomitant expression of CXCR4/CD40 in ovarian carcinoma tissues had stronger correlation with pelvic metastasis than did each alone. It is suggest that SDF-1α acts through CXCR4 to induce ovarian cancer cell migration, which could be facilitated by CD40 activation. Simultaneously examining the expression of CXCR4 and CD40 will provide valuable diagnosis of pelvic metastasis for ovarian carcinomas.

IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8+ T cells.

The effector functions of CD8(+) T cells are influenced by tissue inflammatory microenvironments. IL-33, a member of the IL-1 family, acts as a danger signal after its release during cell necrosis. The IL-33/ST2 axis has been implicated in various Th2 responses. Its role in CD8(+) T-cell-mediated immune response is, however, not known. Here we find that type 1 cytotoxic T (Tc1) cells cultured in vitro unexpectedly express high levels of the IL-33 receptor ST2. Interestingly, the expression of ST2 in Tc1 cells is dependent on T-bet, a master Th1/Tc1 transcription factor. In addition, IL-33 enhances TCR-triggered IFN-γ production. IL-33 together with IL-12 can stimulate IFN-γ production in Tc1 cells. Moreover, IL-33 synergizes with IL-12 to promote CD8(+) T-cell effector function. The synergistic effect of IL-33 and IL-12 is partly mediated by Gadd45b. Together, these in vitro data establish a novel role of IL-33 in promoting effector type 1 adaptive immune responses.

T-bet and eomesodermin are required for T cell-mediated antitumor immune responses.

Cell-mediated adaptive immunity is very important in tumor immune surveillance and tumor vaccination. However, the genetic program underlying an effective adaptive antitumor immunity is elusive. T-bet and Eomesodermin (Eomes) have been suggested to be master regulators of Th1 cells and CD8(+) T cells. However, whether they are important for T cell-mediated antitumor immunity is controversial. In this paper, we show that the combined germline deletion of T-bet and T cell-specific deletion of Eomes resulted in profound defects in adaptive antitumor immune responses. T-bet and Eomes drive Tc1 differentiation by preventing alternative CD8(+) T cell differentiation to Tc17 or Tc2 cells. Surprisingly, T-bet and Eomes are not critical for the generation of systemic CTL activities against cancer cells. Instead, T-bet and Eomes are crucial for tumor infiltration by CD8(+) T cells. This study defines T-bet and Eomes as critical regulators of T cell-mediated immune responses against tumor.

CD256 can be found in antibody-mediated renal allograft rejection tissues.

BACKGROUND: CD256 and CD257 belong to the TNFSF (Tumor necrosis factor superfamily), share closest homology structure, and can form functional heterotrimers. They may be involved in the progression of SLE (Systemic lupus erythematosus), RA (Rheumatoid arthritis), and other autoimmune disorders. In this present study, CD256 and some related molecules were detected and were investigated regarding the potential role of the CD256 signal during the development of renal allograft rejection. METHODS: In 2009, 46 cases of renal allografts were collected, excised for evaluation of dysfunction, and 10 renal protocol biopsies with normal renal function were controlled. Immunohistochemistry (IHC) staining was applied to detect CD256, CD257, C4d, CD138 and other related molecules. HistoQuest Analysis software and SPSS16.0 were used to read and analyse the results. RESULTS: Pathological diagnosis was made according to Banff 2005 guidelines: antibody-mediated rejection (ABMR) 15 cases, T-cell-mediated rejection (TCMR) 16 cases, and 15 unknown aetiology cases (UAC). IHC results showed that CD256, CD257, and receptors for B cell activating factor receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator calcium modulator, and cyclophilin ligand interactor (TACI) were expressed on the membrane/cytoplasm of renal tubular epithelial cells (RTEC) in the ABMR and TCMR group, while these molecules were not or weakly expressed in UAC and protocol biopsies. CD257 strong staining could be seen in ABMR, CD256 strong staining in both BCMR and TCMR, and there was statistical significance compared with other groups (p < 0.05). The receptors BAFF-R, BCMA, and TACI all strongly stained in ABMR, TACI also stained strongly in TCMR, and there was statistical significance compared with other groups (p < 0.05). The CD138+ molecule could be found in the renal interstitium and membrane/cytoplasm of RTEC, the CD138 mean expression in ABMR was statistically higher than other groups (p < 0.05). The correlation analysis indicated that CD256 significantly correlated with BCMA, TACI, and CD138, while CD257 significantly correlated with BAFF-R, BCMA, TACI, and CD138. CONCLUSIONS: CD256 can be found in ABMR tissues and may participate in the progression of ABMR together with CD257.

Analysis of CD8+CD28- T-suppressor cells in gastric cancer patients.

Host anti-tumor immune responses can be attenuated by suppressor T cells of the phenotype CD8(+)CD28(-) (T(s) cells). In the present study, we investigated the presence of CD8(+)CD28(-) (T(s) cells) in the peripheral blood compartment of gastric cancer (GC) patients. Flow cytometry was used to detect the population of CD8(+)CD28(-) T(s) cells present in peripheral blood in therapy naïve patients with gastric cancer (n = 26), postoperative chemotherapy naïve gastric cancer patients (n = 23), and healthy controls (n = 27). Meanwhile, the clinical data of gastric cancer patients were analyzed. A significant difference in the percentage of T(s) cells was observed when comparing peripheral blood samples from cancer patients to healthy volunteers (27.08 ± 1.60% versus 10.86 ± 0.75%). In the patient group, the percentage of CD8(+)CD28(-) cells among lymphocytes was higher in patients with LN metastasis than those without LN metastasis. The percentage of CD8(+)CD28(-) cells was also related to tumor infiltration and size, but not with the degree of differentiation of cancer cells. Moreover, the percentage of CD8(+)CD28(-) cells was higher in preoperative gastric cancer patients (26.24 ± 1.78%) than in those of postoperation patients (15.79 ± 1.11%). These findings may reflect the possibility of tumor-induced immunosuppression, and they should be complemented with further studies.

Effect of tacrolimus on soluble costimulatory molecules in patients with refractory myasthenia gravis.

OBJECTIVES: To investigate the expression and possible role of soluble costimulatory molecules in the treatment of refractory myasthenia gravis. METHODS: Thirty-two patients with refractory myasthenia gravis were enrolled into this study and given tacrolimus 3 mg/day. At the beginning of treatment and 12 months follow-up period, clinical data were collected and recorded. The clinical classification of myasthenia gravis Foundation (MGFA) was performed. The MGFA-quantitative myasthenia gravis score (MGFA-QMGS), manual muscle test (MMT), MG activity of daily living (MG-ADL) and the activity of daily living (MG-ADL), the 15-item myasthenia gravis quality of life (MG QOL-15) and the dose change of prednisone were used to evaluate the efficacy. The expression levels of soluble costimulatory molecules and their ligands (sPD-1/sPD-L1, sICOS/sICOSL, sCD40/sCD40L), soluble CD25 and IL-2 in serum were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed that oral administration of 3 mg tacrolimus daily for 1 year can significantly improve the clinical symptoms of patients with refractory myasthenia gravis, which is characterized by a significant reduction in clinical scores, such as QMG, MMT, ADL, MGQOL-15, and a reduction daily oral prednisolone (PSL) dose (P < 0.0001).We also found that the levels of plasma sPD-1, sCD40, IL-2 in refractory MG patients increased significantly, and those decreased significantly 12 months after tacrolimus treatment (P < 0.05). The level of sCD25 was negatively correlated with clinical severity scores (P < 0.05). After tacrolimus treatment, the level of sPD-L1 increased although there was no significant difference. CONCLUSION: Tacrolimus could relieve the symptoms of refractory MG and significantly decrease the levels of plasma sPD-1, sICOSL, sCD40, sCD25 and IL-2. Soluble costimulatory molecules might be potential biomarkers for MG and tacrolimus treatment.

Overexpression of B7-H4 in tumor infiltrated dendritic cells.

DCs infiltrated tumors appears to be phenotypically and functionally defective. B7-H4 was highlighted for its inhibitory role in T cell responses. In this study, we showed that B7-H4 was moderately expressed in imDCs, and up-regulated by IL-10, and TNF-α could counteract the up-regulatory effects of IL-10 on expression of B7-H4 in DCs in vitro. Furthermore, tumor infiltrated DCs expressed B7-H4 at high levels. Blockade of B7-H4 expressed in DCs highly resulted in enhanced T cell proliferation and IFN-γ production significantly. Otherwise, the high level of IL-10 and TNF-α was both detected in the tumor, which suggested that TNF-α can not antagonize the effects of IL-10 on expression of B7-H4 in DCs in vivo. These data indicate that tumor environment may condition local DCs to become dysfunctional in the phenotype, and that the high expression of B7-H4 may contribute to the tumor infiltrated DCs to mediate immune invasion.

PD-1 blockade combined with IL-33 enhances the antitumor immune response in a type-1 lymphocyte-mediated manner.

PD-1 immune checkpoint blockade and cytokine IL-33 have shown significant therapeutic effects in tumor immunotherapy. These therapies promote CD8+ T cell activation, proliferation, and effector functions. However, there were few research about the combined therapy efficacy. In this study, we established B16-empty vector and B16-IL33 melanoma mouse models and treated with PD-1 monoclonal antibody. We reported that PD-1 blockade combined with cytokine IL-33 further inhibited tumor progression and prolonged the survival of tumor-bearing mice. Mechanistically, the combination therapy was found to further facilitate CD4+ and CD8+ T lymphocytes accumulation, and enhance the antitumor effects of CD4+or CD8+tumor-infiltrating lymphocytes by promoting type-1 immune response within the tumor microenvironment using flow cytometry and quantitative real time polymerase chain reaction. Thus, PD-1 blockade combined with IL-33 has application potential in tumor immunotherapy. Further, this study provides a new promising strategy and theoretical basis for tumor combination immunotherapy.

Eomes Impedes Durable Response to Tumor Immunotherapy by Inhibiting Stemness, Tissue Residency, and Promoting the Dysfunctional State of Intratumoral CD8+ T Cells.

Sustaining efficacious T cell-mediated antitumor immune responses in the tumor tissues is the key to the success of cancer immunotherapy. Current strategies leverage altering the signals T cells sense in the tumor microenvironment (TME). Checkpoint inhibitor-based approaches block inhibitory signals such as PD-1 whereas cytokine-based therapies increase the level of immune-stimulatory cytokines such as IL-2. Besides extrinsic signals, the genetic circuit within T cells also participates in determining the nature and trajectory of antitumor immune responses. Here, we showed that efficacy of the IL33-based tumor immunotherapy was greatly enhanced in mice with T cell-specific Eomes deficiency. Mechanistically, we demonstrated that Eomes deficient mice had diminished proportions of exhausted/dysfunctional CD8+ T cells but increased percentages of tissue resident and stem-like CD8+ T cells in the TME. In addition, the IFNγ+TCF1+ CD8+ T cell subset was markedly increased in the Eomes deficient mice. We further demonstrated that Eomes bound directly to the transcription regulatory regions of exhaustion and tissue residency genes. In contrast to its role in inhibiting T cell immune responses at the tumor site, Eomes promoted generation of central memory T cells in the peripheral lymphoid system and memory recall responses against tumor growth at a distal tissue site. Finally, we showed that Eomes deficiency in T cells also resulted in increased efficacy of PD-1-blockade tumor immunotherapy. In all, our study indicates that Eomes plays a critical role in restricting prolonged T cell-mediated antitumor immune responses in the TME whereas promoting adaptive immunity in peripheral lymphoid organs.

Gadd45b and Gadd45g are important for anti-tumor immune responses.

An effective Th1 type cell-mediated immune response against cancer cells is critical in limiting cancer progression. Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate. More importantly, the tumor vaccination, which is effective in WT mice, failed in Gadd45b/Gadd45g doubly deficient mice. Collectively, these data demonstrate that members of the Gadd45 gene family are important for anti-tumor immune responses.

Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer.

To establish the prognostic value of B7-H4 expression by tumor cells in gastric cancer patients, we evaluated the association of B7-H4 expression with clinicopathologic factors and overall survival of gastric cancer patients. A retrospective cohort study including 156 gastric cancer patients was performed in the present report. Immunohistochemical assay was used to evaluate the expression of B7-H4 in the surgical specimens of gastric cancer tissues. Multi-univariate COX model was then used to evaluate the association of B7-H4 expression with the patients' survival and clinicopathological parameters. B7-H4 expression in the gastric cancer cells was observed in about 44.9% gastric cancer specimens. Univariate analysis demonstrated that there was no correlation between B7-H4 expression and sex, age, histological type, pathological grade or tumor size. In contrast, B7-H4 expression correlated positively with cancer invasiveness and lymph node metastasis. In addition, the median overall survival time of patients with lower B7-H4 expression was 13 months longer than that of patients with higher expression (chi(2) = 12.38, P < 0.0001), and the median disease-free survival time of patients with lower B7-H4 expression was significantly longer than that of patients with higher expression (33 vs. 16 months, chi(2) = 14.977, P < 0.0001). After adjustment for other confounding factors, the COX model analysis indicated that the death risk was significantly higher in patients with higher B7-H4 expression than those with lower expression (RR = 1.85, 95% CI = 1.15-2.96). The present study demonstrated that higher B7-H4 expression in cancer cells was associated with poor prognosis of gastric cancer patients. This is consistent with the idea that B7-H4 promotes cancer progression, likely via inhibition of anti-tumor immune responses.

Association between interleukin-36γ and tumor progression in non-small cell lung cancer.

Immunotherapy is effective in improving the survival and prognosis of patients with non-small cell lung cancer (NSCLC), and identifying effective immunomarkers is important for immunotherapy. Interleukin (IL)-36γ is a novel immunomarker that has an important function in the antitumor immune response. The present study investigated the association between IL-36γ and NSCLC to provide novel insight into immunotherapy for patients with NSCLC. Tissue microarrays of lung adenocarcinoma and squamous cell carcinoma were purchased for immunohistochemical analysis of IL-36γ expression levels and clinical parameters. In addition, fresh clinical NSCLC and adjacent normal tissue samples were collected to analyze IL-36γ mRNA expression levels using quantitative PCR. IL-36γ protein was primarily located in the cytoplasm, with a small quantity in the nucleus, and IL-36γ mRNA and protein expression levels in lung cancer tissues were significantly higher compared with those in adjacent normal tissues. Elevated IL-36γ protein expression levels were significantly associated with a higher tumor grade of lung adenocarcinoma; however, IL-36γ mRNA expression levels were inversely associated with the clinical Tumor-Node-Metastasis stage in patients with lung squamous cell carcinoma. In addition, patients with adenocarcinoma with high IL-36γ protein expression levels tended to longer post-operative survival times. These findings indicate that IL-36γ may have potential as an immunomarker for prediction of tumor progression and survival in patients with NSCLC.