Second-generation checkpoint inhibitors and Treg depletion synergize with a mouse cancer vaccine in accordance with tumor microenvironment characterization.

BACKGROUND: Despite advances in checkpoint inhibitor (CPI) therapy for cancer treatment, many cancers remain resistant. Tumors deemed "cold" based on lack of T cell infiltration show reduced potential for CPI therapy. Cancer vaccines may overcome the inadequacy of existing T cells by inducing the needed antitumor T cell response to synergize with CPIs and overcome resistance. METHODS: CT26 and TC1 tumor cells were injected subcutaneously into mice. Mice were treated with combinations of CPIs alone or a cancer vaccine specific to the tumor antigen E7 present in TC1 cells. CPIs for the TC1 model were selected because of immunophenotyping TC1 tumors. Antitumor and protumor immunity, tumor size and survival, sequence and timing of vaccine and CPI administration, and efficacy of treatment in young and aged mice were probed. RESULTS: While "hot" CT26 tumors are treatable with combinations of second-generation CPIs alone or with anti-TGFß, "cold" TC1 tumor reduction requires the synergy of a tumor-antigen-specific vaccine in combination with two CPIs, anti-TIGIT and anti-PD-L1, predicted by tumor microenvironment (TME) characterization. The synergistic triple combination delays tumor growth better than any pairwise combination and improves survival in a CD8+T cell-dependent manner. Depletion of CD4+T cells improved the treatment response, and depleting regulatory T cells (Treg) revealed Tregs to be inhibiting the response as also predicted from TME analysis. We found the sequence of CPI and vaccine administration dictates the success of the treatment, and the triple combination administered concurrently induces the highest E7-specific T cell response. Contrary to young mice, in aged mice, the cancer vaccine alone is ineffective, requiring the CPIs to delay tumor growth. CONCLUSIONS: These findings show how pre-existing or vaccine-mediated de novo T cell responses can both be amplified by and facilitate synergistic CPIs and Treg depletion that together lead to greater survival, and how analysis of the TME can help rationally design combination therapies and precision medicine to enhance clinical response to CPI and cancer vaccine therapy.

Overexpression of Semaphorin 3A is a Marker Associated with Poor Prognosis in Patients with Nasopharyngeal Carcinoma.

Semaphorins were discovered as guidance signals that mediate neural development. Recent studies suggest that semaphorin 3A (Sema3A), a member of the semaphorin family, is involved in the development of several cancers. This study aimed to analyze the association of Sema3A with the clinical features of nasopharyngeal carcinoma (NPC), an Epstein-Barr virus-associated carcinoma, and the Epstein-Barr virus primary oncogene latent membrane protein 1 (LMP1). The expression of Sema3A and LMP1 was immunohistochemically examined in the 35 NPC specimens. The mean expression scores for Sema3A and LMP1 were 20.8% ± 14.5% and 13.9% ± 14.8%, respectively. The expression of Sema3A significantly correlated with that of LMP1 (r = 0.41, p = 0.014). In addition, the Sema3A high cohort showed significantly poorer prognosis than the Sema3A low cohort. Sema3A expression was higher in the LMP1-positive KH-1 and KR-4 cell lines compared to the LMP1-negative HeLa cells. Overexpression of LMP1 in the LMP1-negative AdAH cell line upregulated Sema3A expression, both at the transcriptional and translational level. Finally, Sema3A expression was associated with poor prognosis in patients with NPC. Our data suggest that LMP1 induces the expression of Sema3A, which may promote tumor progression in NPC.

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior.

Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 genes are associated with multiple neurological and psychiatric conditions, including autism spectrum disorder, Parkinson's disease, and schizophrenia. In addition, both antigens are related to infectious and immunoregulational processes. The most important clues to demonstrate how these molecules play a role in the brain are oxytocin (OT) and the OT system. OT is axo-dendritically secreted into the brain from OT-containing neurons and causes activation of OT receptors mainly on hypothalamic neurons. Here, we overview the CD38/CD157-dependent OT release mechanism as the initiation step for social behavior. The receptor for advanced glycation end-products (RAGE) is a newly identified molecule as an OT binding protein and serves as a transporter of OT to the brain, crossing over the blood-brain barrier, resulting in the regulation of brain OT levels. We point out new roles of CD38 and CD157 during neuronal development and aging in relation to nicotinamide adenine dinucleotide+ levels in embryonic and adult nervous systems. Finally, we discuss how CD38, CD157, and RAGE are crucial for social recognition and behavior in daily life.

Expression and subcellular localisation of AID and APOBEC3 in adenoid and palatine tonsils.

Activation-induced cytidine deaminase (AID) and apolipoprotein B mRNA-editing catalytic polypeptide 3 (A3) family are cytidine deaminases that play critical roles in B-cell maturation, antiviral immunity and carcinogenesis. Adenoids and palatine tonsils are secondary lymphoid immune organs, in which AID and A3s are thought to have several physiological or pathological roles. However, the expression of AID or A3s in these organs has not been investigated. Therefore, we investigated the expression profiles of AID and A3s, using 67 samples of adenoids and palatine tonsils from patients, with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analyses. AID and A3s expression levels in the adenoids and the palatine tonsils of the same individual significantly correlated with each other. Of note, AID expression level in the adenoids negatively correlated with the age (r = -0.373, P = 0.003). The younger group with adenoid vegetation and tonsillar hypertrophy showed more abundant AID expression than the older group with recurrent tonsillitis and peritonsillar abscesses (P = 0.026). Moreover, immunohistochemical analysis revealed the distribution of AID and A3s in the epithelial cells as well as germinal centres. The localisation of AID expression and its relation to age may contribute to adenoid vegetation and inflammation.

Expression of interferon regulatory factor 7 correlates with the expression of Epstein-Barr Virus latent membrane protein 1 and cervical lymph node metastasis in nasopharyngeal cancer.

Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV-associated NPC.

EBV infection is prevalent in the adenoid and palatine tonsils in adults.

Epstein-Barr virus (EBV) is associated with the pathogenesis of several diseases in both adults and children. However, there have been no reports on the prevalence and amount of EBV in the adenoids of adults; thus, it is important to investigate these in the adenoids and tonsils of adults and children. In this study, 67 patients who underwent tonsillectomy or adenotonsillectomy were included and divided into two groups: adults aged ≥ 16 years (n = 35) and children aged <16 years (n = 32). Patients' adenoid and tonsil tissues were analyzed using quantitative polymerase chain reaction for EBV DNA. EBV was detected in 26 (74%) adenoids and 25 (71%) tonsils among the adult group and was detected 21 (66%) adenoids and 20 (63%) tonsils in the child group. There was no significant difference in EBV DNA prevalence between the adenoids and tonsils for each group. However, there was a significant correlation between EBV DNA load in the adenoids and tonsils of the same individual in both groups (r = 0.579, P < 0.01, adult group; r = 0.919, P < 0.01, child group). In conclusion, EBV infection is prevalent in the adenoids and tonsils in adults and children. These results indicate that EBV continuously reside in the nasopharyngeal region after primal infection and may develop several diseases.