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Simple Summary: Cancer in the head and neck region (HNSCC) is exponentially increasing due to human papillomavirus (HPV) infections. This paper helps us to understand the complexity of the inflammatory networks and the mechanisms of immune evasion in HPV+ HNSCC to open up new avenues and drive the discovery of useful tools to be translated clinically in the screening and treatment of these cases, especially to overcome resistance and improve patients' quality of life. Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC. [ABSTRACT FROM AUTHOR]

Objective: Silibinin has exhibited antitumor activities. However, there are few reports about the immunomodulatory properties of silibinin on T lymphocyte function in the tumor microenvironment. Here, we determined the effects of silibinin on T cells of peripheral blood mononuclear cells (PBMCs), cultivated alone or with a human cell line of glioblastoma (U-87 MG). Materials and Methods: The proliferation of T lymphocytes was assessed by MTT test in the presence of silibinin (15 and 45 µM). Also, total antioxidant capacity (TAC), the activity of superoxide dismutase-3 (SOD3), and the levels of two cytokines interferon gamma (IFN-γ) and tumor growth beta (TGF-β) were compared between treated and untreated PBMCs alone or co-cultured with U-87 cells. Results: According to our results, silibinin raised the TAC levels and SOD3 activity in the PBMCs and in the co-culture condition. Moreover, silibinin-treated PBMCs showed higher IFN-γ levels and lower TGF-β levels. Interestingly, silibinin protected PBMCs against the U-87-induced suppression. Conclusion: Altogether, these results proposed the immunomodulatory potential of silibinin on T cells of PBMCs, as well as its partially protective effects on PBMCs against the suppression induced by U-87 MG cells. [ABSTRACT FROM AUTHOR]

Background: Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway-related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear.Methods: Transcriptomic analysis was conducted using The Cancer Genome Atlas datasets. The effect of JNK-IN-8, a covalent pan-JNK inhibitor, on TNBC tumor growth, lung metastasis, and the TME was measured in TNBC syngeneic mouse models (n = 13 per group). Tumor (n = 43) or serum (n = 46) samples from TNBC patients were analyzed using multiplex immunohistochemistry or Luminex assay. All statistical tests were 2-sided.Results: CIBERSORT analysis revealed that TNBC patients with high phosphorylated JNK level (n = 47) had more regulatory T cell (Treg) infiltration than those with a low phosphorylated JNK level (n = 47) (P = .02). Inhibition of JNK signaling statistically significantly reduced tumor growth (P < .001) and tumor-infiltrating Tregs (P = .02) while increasing the infiltration of CD8+ T cells in TNBC mouse models through the reduction of C-C motif ligand 2 (CCL2). Tumor-associated macrophages were the predominant cells secreting CCL2, and inhibition of JNK signaling reduced CCL2 secretion of human primary macrophages. Moreover, in patients with TNBC (n = 43), those with high levels of CCL2+ tumor-associated macrophages had more Treg and less CD8+ T cell infiltration (P = .04), and the serum CCL2 level was associated with poor overall survival (hazard ratio = 2.65, 95% confidence interval = 1.29 to 5.44, P = .008) in TNBC patients (n = 46).Conclusions: The JNK/C-JUN/CCL2 axis contributes to TNBC aggressiveness via forming an immunosuppressive TME and can offer novel therapeutic strategies for TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. Immune checkpoint inhibitor (ICI) therapy has made progress in TNBC treatment. PD-L1 expression is a useful biomarker of ICI therapy efficacy. However, tumor-immune microenvironment (TIME) factors, such as immune cell compositions and tumor-infiltrating lymphocyte (TIL) status, also influence tumor immunity. Therefore, it is necessary to seek biomarkers that are associated with multiple aspects of TIME in TNBC. In this study, we developed an immune-related gene prognostic index (IRGPI) with a substantial prognostic value for TNBC. Moreover, the results from multiple cohorts reproducibly demonstrate that IRGPI is significantly associated with immune cell compositions, the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression in TIME. Therefore, IRGPI is a promising biomarker closely related to patient survival and TIME of TNBC and may have a potential effect on the immunotherapy strategy of TNBC. Tumor-immune cell compositions and immune checkpoints comprehensively affect TNBC outcomes. With the significantly improved survival rate of TNBC patients treated with ICI therapies, a biomarker integrating multiple aspects of TIME may have prognostic value for improving the efficacy of ICI therapy. Immune-related hub genes were identified with weighted gene co-expression network analysis and differential gene expression assay using The Cancer Genome Atlas TNBC data set (n = 115). IRGPI was constructed with Cox regression analysis. Immune cell compositions and TIL status were analyzed with CIBERSORT and TIDE. The discovery was validated with the Molecular Taxonomy of Breast Cancer International Consortium data set (n = 196) and a patient cohort from our hospital. Tumor expression or serum concentrations of CCL5, CCL25, or PD-L1 were determined with immunohistochemistry or ELISA. The constructed IRGPI was composed of CCL5 and CCL25 genes and was negatively associated with the patient's survival. IRGPI also predicts the compositions of M0 and M2 macrophages, memory B cells, CD8+ T cells, activated memory CD4 T cells, and the exclusion and dysfunction of TILs, as well as PD-1 and PD-L1 expression of TNBC. IRGPI is a promising biomarker for predicting the prognosis and multiple immune characteristics of TNBC. [ABSTRACT FROM AUTHOR]