Soluble CD27 as a predictive biomarker for intra-tumoral CD70/CD27 interaction in nasopharyngeal carcinoma.

In CD70-expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27-positive lymphocytes infiltrate around tumor cells. NPC patients with CD27-positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27-positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70-positive NPC with CD27-positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27-targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC.

Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area.

BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

Efficacy of Cetuximab Combined with Paclitaxel in Patients with Recurrent Salivary Gland Carcinoma: A Retrospective Observational Study.

INTRODUCTION: Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy for patients with SGC. Our study described promising results of epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel in patients with SGC. METHODS: The medical records of patients with recurrent SGC treated with weekly cetuximab combined with paclitaxel (Cmab-PTX) between December 2017 and December 2022 at our institutions were retrospectively analyzed. RESULTS: Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months (range of 2-36 months). The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response and disease control rates were 71.4% and 85.7%, respectively. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. CONCLUSION: Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC. Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy in patients with SGC. Our study described promising results of cetuximab (Cmab), epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel (PTX) in patients with SGC. Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months. The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response rate was 71.4%. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. Our study revealed a preferable objective response rate of Cmab-PTX for patients with high-grade SGC. Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC.

Prognostic Value of the 18F-FDG PET/CT and Haematological Parameters in Head and Neck Cancer.

INTRODUCTION: Fluorine 18-fluoro-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used for the staging of head and neck cancer. This study aimed to evaluate the correlation between 18F-FDG PET/CT, haematological parameters and prognosis in patients with advanced head and neck cancer. METHODS: This was a single-institutional retrospective study of 83 patients with advanced head and neck squamous cell carcinoma (HNSCC) who underwent 18F-FDG PET/CT imaging before initial treatment between 2014 and 2018. 18F-FDG PET/CT after treatment was performed in 57 patients. The prognostic parameters of the pre- and post-treatment maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) of primary tumours and haematological parameters were analysed to evaluate the association between overall survival (OS) and progression-free survival (PFS). RESULTS: Pre-MTV, pre-TLG and post-SUVmax were significantly associated with poor OS and PFS (p < 0.05). Haematological parameters, including pretreatment neutrophil/lymphocyte ratio and C-reactive protein/albumin ratio, were associated with 18F-FDG PET/CT parameters. In multivariate analysis, post-SUVmax was an independent prognostic factor for OS and PFS. CONCLUSION: A correlation between PET/CT metabolic and haematological parameters was observed. The volume and intensity of 18F-FDG uptake region, in addition to haematological parameters, are feasible markers for predicting the progression of HNSCC in daily practice. Further, post-SUVmax could be an independent parameter for predicting poor survival.

Mitogen-activated protein kinase inhibition augments the T cell response against HOXB7-expressing tumor through human leukocyte antigen upregulation.

Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7-expressing tumors through immune cells. A novel HOXB7-derived peptide epitope (HOXB78-25 ) elicited antigen-specific and tumor-reactive promiscuous CD4+ T cell responses. These CD4+ T cells produced γ-interferon (IFN-γ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK. Mitogen-activated protein kinase inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide-based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment.

Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer.

Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.

Expression of soluble CD27 in extranodal natural killer/T-cell lymphoma, nasal type: potential as a biomarker for diagnosis and CD27/CD70-targeted therapy.

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

[Treatment Experience of Chemotherapy and Carbon-Ion Radiotherapy followed by Curative Conversion Surgery for Initially Locally Advanced Unresectable Pancreatic Cancer after Distal Gastrectomy].

BACKGROUND: Carbon-ion radiotherapy(CIRT)has an advantage over conventional radiotherapy by its dose distribution and biological effect for locally advanced unresectable pancreatic cancer(UR-PC). Conversion surgery(CS)might be attempted for UR-PC with favorable response by chemotherapy and radiotherapy. CASE PRESENTATION: A 67-year-old female who have a history of distal gastrectomy. CT scan revealed locally advanced UR-PC with invasion to celiac artery, 60 mm in size. Systemic chemotherapy with gemcitabine and nab-paclitaxel was continued for 15 months, showing decrease of tumor markers and radiological shrinkage of the tumor. The patient was referred to our hospital for surgical consultation. Since there was no metastasis in staging laparoscopy, CIRT with gemcitabine was administered for 3 weeks. After completion of CIRT, distal pancreatectomy with celiac axis resection and total remnant gastrectomy for direct invasion of the tumor was performed as CS, resulting R0 resection. Her postoperative course was uneventful with 17 days of hospital stay. DISCUSSION: CS after CIRT was safely performed. Clinical trial of total neoadjuvant therapy with systemic chemotherapy, CIRT, followed by CS for locally advanced CIRT is ongoing in our hospital. CIRT could be an effective treatment in locally advanced UR-PC in the context of multi-modal treatment including CS.

[A Case of Long-Term Survival by Multidisciplinary Surgical Treatment for Metastatic Multi-Organ Metastasis after Radical Resection of Esophageal Cancer].

A 78-year-old man with advanced thoracic esophageal cancer underwent radical esophagectomy after neoadjuvant chemotherapy with cisplatin plus 5-FU. He had left adrenal metastasis 10 months after surgery and removed it, but 3 months later he had liver metastases. After 2 courses of chemotherapy with nedaplatin plus 5-FU, resection was performed. One course of nedaplatin plus 5-FU for adjuvant chemotherapy was added, but the patient was followed up without another chemotherapy after surgery because of intestinal obstruction due to infection and increase of the lymphatic cyst in the abdominal cavity. Six months after the liver resection, nodules appeared in the right lung, and 4 months later, multiple nodules extending to both lungs were observed. Therefore, it was judged that there were multiple lung metastases, and administration of nivolumab was started. He has been 3 years since the recurrence of esophageal cancer and 17 months after the start of nivolumab administration, but the recurrence lesion is only progressing to lung metastasis.

Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery.

Identification of immunogenic tumor antigens, their corresponding T cell epitopes and the selection of effective adjuvants are prerequisites for developing effective cancer immunotherapies such as therapeutic vaccines. Murine double minute 2 (MDM2) is an E3 ubiquitin-protein ligase that negatively regulates tumor suppressor p53. Because MDM2 overexpression serves as a poor prognosis factor in various types of tumors, it would be beneficial to develop MDM2-targeted cancer vaccines. In this report, we identified an MDM2-derived peptide epitope (MDM232-46) that elicited antigen-specific and tumor-reactive CD4+ T cell responses. These CD4+ T cells directly killed tumor cells via granzyme B. MDM2 is expressed in head and neck cancer patients with poor prognosis, and the T cells that recognize this MDM2 peptide were present in these patients. Notably, Nutlin-3 (MDM2-p53 blocker), inhibited tumor cell proliferation, was shown to augment antitumor T cell responses by increasing MDM2 expression, HLA-class I and HLA-DR through class II transactivator (CIITA). These results suggest that the use of this MDM2 peptide as a therapeutic vaccine combined with MDM2 inhibitors could represent an effective immunologic strategy to treat cancer.