TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway

Background Worldwide, Breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer that PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. Methods and Result In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulate the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression that p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation, invasion, and promote apoptosis in breast cancer cells. Conclusions In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

ERBB3 Methylation and Immune Infiltration in Tumor Microenvironment of Cervical Cancer

ERBB3, a member of the ERBB family of receptor tyrosine kinases, plays an important role in cancer, despite its lack of intrinsic Carcinogenic mechanism of CESC. Research on bioinformatics methods through multi-omics, this work proves that ERBB3 gene mutation, methylation modification have extensive regulatory mechanisms on the CESC microenvironment. We found that ERBB3 is involved in carcinogenesis of cervical cancer and is not associated with its prognosis. The carcinogenic mechanism is mainly related to the suppression of the immune system between TILS and the methylation of the RNA level. Our study indicated ERBB3 is more likely to be a carcinogenic factor than a key prognostic factor for cervical cancer. Methylation of ERBB3 may work as a chekpoint immunotherapy target in CESC, DNA methylation modification of the 4480 base pair downstream of ERBB3 transcription initiation site was the highest.

The cGAS-STING Pathway: A Promising Immunotherapy Target

With the continuous development of immunotherapy, researchers have paid more attention to the specific immune regulatory mechanisms of various immune responses in different diseases. As a novel and vital innate immune signal pathway, the cGAS-STING signal pathway activated by nucleic acid substances, interplays with other immune responses, by which it participates in regulating cancer, autoimmune and inflammatory diseases, microbial and parasitic infectious diseases, and other diseases. With the exception of its role in innate immunity, the growing list of researches demonstrated expanding roles of the cGAS-STING signal pathway in bridging the innate immunity (macrophage polarization) with the adaptive immunity (T lymphocytes differentiation). Macrophages and T lymphocytes are the most representative cells of innate immunity and adaptive immunity, respectively. Their polarization or differentiation are involved in the pathogenesis and progression of various diseases. Here we mainly summarized recent advanced discoveries of how the cGAS-STING signal pathway regulated macrophages polarization and T lymphocytes differentiation in various diseases and vaccine applications, providing a promising direction for the development and clinical application of immunotherapeutic strategies for related diseases.

Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment

In recent years, it became apparent that cancers either associated with viral infections or aberrantly expressing endogenous retroviral elements (EREs) are more immunogenic, exhibiting an intense intra-tumor immune cell infiltration characterized by a robust cytolytic apparatus. On the other hand, epigenetic regulation of EREs is crucial to maintain steady-state conditions and cell homeostasis. In line with this, epigenetic disruptions within steady-state cells can lead to cancer development and trigger the release of EREs into the cytoplasmic compartment. As such, detection of viral molecules by intracellular innate immune sensors leads to the production of type I and type III interferons that act to induce an antiviral state, thus restraining viral replication. This knowledge has recently gained momentum due to the possibility of triggering intratumoral activation of interferon responses, which could be used as an adjuvant to elicit strong anti-tumor immune responses that ultimately lead to a cascade of cytokine production. Accordingly, several therapeutic approaches are currently being tested using this rationale to improve responses to cancer immunotherapies. In this review, we discuss the immune mechanisms operating in viral infections, show evidence that exogenous viruses and endogenous retroviruses in cancer may enhance tumor immunogenicity, dissect the epigenetic control of EREs, and point to interferon pathway activation in the tumor milieu as a promising molecular predictive marker and immunotherapy target. Finally, we briefly discuss current strategies to modulate these responses within tumor tissues, including the clinical use of innate immune receptor agonists and DNA demethylating agents.

Identification of TNFAIP8 as an Immune-Related Biomarker Associated With Tumorigenesis and Prognosis in Cutaneous Melanoma Patients

Tumor necrosis factor-α–induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which is associated with inflammation and tumorigenesis. The potential role of TNFAIP8 in a tumor immune microenvironment in skin cutaneous melanoma (SKCM) has not yet been investigated. The TNFAIP8 expression was evaluated via gene expression profiling interactive analysis (GEPIA). We also evaluated the influence of TNFAIP8 on overall survival via GEPIA and PrognoScan. After GO and KEGG pathway analyses, the correlation between the TNFAIP8 expression level and immune cells or gene markers of the immune infiltration level was explored by R-language. The result showed the TNFAIP8 expression was significantly reduced in SKCM in comparison with normal control. In SKCM, the TNFAIP8 expression in higher levels was associated with the better overall survival. The high expression of TNFAIP8 was positively correlated with the immune score and promoted immune cell infiltration in SKCM patients. TNFAIP8 can be a positive prognosis marker or new immunotherapy target in SKCM.

Molecular and Clinical Characterization of a Novel Prognostic and Immunologic Biomarker GPSM3 in Low-Grade Gliomas

Background: as the most common malignancy of the central nervous system, low-grade glioma (LGG) patients suffered a poor prognosis. Tumor microenvironment, especially immune components, plays an important role in the progression of tumors. Thus, it is critical to explore the key immune-related genes, a comprehensive understanding of the TME in LGG helps us find novel cancer biomarkers and therapeutic targets. Methods: the GPSM3 expression level and the correlations between clinical characteristics and GPSM3 levels were analyzed with the data from CGGA and TCGA dataset. Univariate and multivariate cox regression model were built to predict the prognosis of LGG patients with multiple factors. Then the correlation between GPSM3 with immune cell infiltration was explored by ESTIMATE, CIBERSORT and TIMER2.0. At last, the correlation analyzed between GPSM3 expression and immune checkpoint related genes were also analyzed. Results: GPSM3 expression was overexpressed in LGG and negatively correlated to the GPSM3 DNA methylation. Univariate and multivariate Cox analysis demonstrated that GPSM3 expression was an independent prognostic factor in LGG patients. Functional characterization of GPSM3 revealed that it was associated with many immune processes to tumor cells. GPSM3 expression was positive related to the immune score, Stromal scores and ESTIMATE scores, but negative related to the Tumor purity. Immune features in the TME of GPSM3-high LGG group is characterized by a higher infiltrating of regulatory T cells, neutrophils, macrophages M2, and a lower proportion of monocytes than to the GPSM3-low group. Furthermore, GPSM3 expression exhibited significant correlations with the immune checkpoint-related genes, especially PD-1, PD-L1, PD-L2, CTLA4 and TIM3. Conclusions: these findings proved that GPSM3 could serve as a prognostic biomarker and potential immunotherapy target for LGG.