Identification of triciribine as a novel myeloid cell differentiation inducer.

Differentiation therapy using all-trans retinoic acid (ATRA) for acute promyelocytic leukemia (APL) is well established. However, because the narrow application and tolerance development of ATRA need to be improved, we searched for another efficient myeloid differentiation inducer. Kinase activation is involved in leukemia biology and differentiation block. To identify novel myeloid differentiation inducers, we used a Kinase Inhibitor Screening Library. Using a nitroblue tetrazolium dye reduction assay and real-time quantitative PCR using NB4 APL cells, we revealed that, PD169316, SB203580, SB202190 (p38 MAPK inhibitor), and triciribine (TCN) (Akt inhibitor) potently increased the expression of CD11b. We focused on TCN because it was reported to be well tolerated by patients with advanced hematological malignancies. Nuclear/cytoplasmic (N/C) ratio was significantly decreased, and myelomonocytic markers (CD11b and CD11c) were potently induced by TCN in both NB4 and acute myeloid leukemia (AML) M2 derived HL-60 cells. Western blot analysis using NB4 cells demonstrated that TCN promoted ERK1/2 phosphorylation, whereas p38 MAPK phosphorylation was not affected, suggesting that activation of the ERK pathway is involved in TCN-induced differentiation. We further examined that whether ATRA may affect phosphorylation of ERK and p38, and found that there was no obvious effect, suggesting that ATRA induced differentiation is different from TCN effect. To reveal the molecular mechanisms involved in TCN-induced differentiation, we performed microarray analysis. Pathway analysis using DAVID software indicated that "hematopoietic cell lineage" and "cytokine-cytokine receptor interaction" pathways were enriched with high significance. Real-time PCR analysis demonstrated that components of these pathways including IL1ß, CD3D, IL5RA, ITGA6, CD44, ITGA2B, CD37, CD9, CSF2RA, and IL3RA, were upregulated by TCN-induced differentiation. Collectively, we identified TCN as a novel myeloid cell differentiation inducer, and trials of TCN for APL and non-APL leukemia are worthy of exploration in the future.

Regulatory T-cells activated in metastatic draining lymph nodes possibly suppress cancer immunity in cancer tissues of head and neck squamous cell cancer.

Regulatory T cells (Tregs) play an important role in creating an immunosuppressive microenvironment in cancer tissues. However, the mechanisms by which Tregs are activated and suppress cancer immunity remain unclear. To elucidate these mechanisms, we performed a T cell receptor (TCR) repertoire analysis of Tregs and conventional T cells in peripheral blood, draining lymph nodes (DLNs), and cancer tissues of patients with head and neck squamous cell cancer (HNSCC). We found that the TCR repertoire was skewed in cancer tissue and metastatic DLNs (M-DLNs) compared with non-metastatic DLNs, and TCR repertoire similarities in Tregs and CD8+ T cells between M-DLNs and cancer tissue were high compared with those at other sites. These results suggest that Tregs and CD8+ T cells are activated in M-DLNs and cancer tissues by cancer antigens, such as neoantigens, and shared antigens and Tregs suppress CD8+ T cell function in a cancer antigen-specific manner in M-DLNs and cancer tissue. Moreover, M-DLNs might be a source of Tregs and CD8+ T cells recruited into the cancer tissue. Therefore, targeting Tregs in M-DLNs in an antigen-specific manner is expected to be a novel immunotherapeutic strategy for HNSCCs.

Fucosylation inhibitor 6-alkynylfucose enhances the ATRA-induced differentiation effect on acute promyelocytic leukemia cells.

For acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) is well established. However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we investigated the effects of combinations of glycosylation inhibitors with ATRA to achieve better efficiency than ATRA alone. We found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) and ATRA had an additional effect on cell differentiation, as revealed by expression changes in two differentiation markers, CD11b and CD11c, and significant morphological changes in NB4 APL and HL-60 acute myeloid leukemia (AML) cells. In AAL lectin blot analyses, ATRA or 6AF alone could decrease fucosylation, while their combination decreased fucosylation more efficiently. To clarify the molecular mechanism for the 6AF effect on ATRA-induced differentiation, we performed microarray analyses using NB4 cells. In a pathway analysis using DAVID software, we found that the C-type lectin receptor (CLR) signaling pathway was enriched with high significance. In real-time PCR analyses using NB4 and HL-60 cells, FcεRIγ, CLEC6A, CLEC7A, CASP1, IL-1ß, and EGR3, as components of the CLR pathway, as well as CD45 and AKT3 were upregulated by 6AF in ATRA-induced differentiation. Taken together, the present findings suggest that the CLR signaling pathway is involved in the 6AF effect on ATRA-induced differentiation.

Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor ß and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor ß and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor ß after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor ß-STAT3 and PDGF-PDGF receptor ß-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.

Immune Status of Cervical Lymph Nodes in Head and Neck Cancer-A Surgical Oncology Perspective.

Neck dissection for cervical lymph node metastasis is an established procedure for head and neck cancer (HNC). However, with the advent of immunotherapy, head and neck surgical oncologists need to rethink removing all lymph nodes, including those with immune function. We investigated the anti-cancer immune response of the cervical lymph nodes in four patients with human papillomavirus type 16 (HPV16)-positive head and neck squamous cell carcinoma. Using lymphocytes extracted from local, metastatic, and non-metastatic lymph nodes and peripheral blood from these patients, we performed an intracellular flow cytometric cytokine assay using anti-IFNγ and anti-TNF-α monoclonal antibodies to detect HPV16 E6- and E7-specific T cells. HPV status and p16 immunostaining were determined by in situ detection using the HPV RNAscope method and immunohistochemistry. In one case, E6-specific and E7-specific CD8+ T cells were detected in proximal metastatic nodes and distal non-metastatic nodes. This finding suggests that non-metastatic nodes should be preserved for their immune function during neck dissection and that the immune function of non-metastatic lymph nodes is important when administering immunotherapy. In this context, head and neck surgical oncologists treating HNC should consider the place of immunotherapy and neck dissection in the treatment of HNC.

Artesunate and cisplatin synergistically inhibit HNSCC cell growth and promote apoptosis with artesunate­induced decreases in Rb and phosphorylated Rb levels.

In the treatment of head and neck cancer, cisplatin is often used as a therapeutic agent; however, its efficacy is limited and it can cause renal dysfunction as an adverse effect. For this reason, the use of cisplatin is limited in elderly patients with reduced renal function. Recently, artemisinin, which was developed as an antimalarial drug, was found to have antitumor effects and is effective in combination with other anticancer drugs. In the present study, the antitumor effects of artemisinin and its derivatives as well as their combination with cisplatin and iron on head and neck squamous cell carcinoma cell lines, were investigated. Cell viability was determined by a cell viability assay, the cell cycle was analyzed by flow cytometry, cell death was assessed with annexin V and propidium iodide staining, and western blotting was used to analyze retinoblastoma protein (Rb), phosphorylated (p­)Rb, and other cell cycle­associated molecules. A total of four artemisinin compounds were examined and it was found that artesunate and dihydroartemisinin had a significant inhibitory effect on growth. It was also identified that the combination of artesunate, cisplatin, and iron inhibited cell proliferation and caused S/G2­M cell cycle arrest. In addition, western blotting of Rb, a molecule involved in the cell cycle, showed that artesunate induced the loss of not only Rb but also p­Rb. These results suggested that artesunate is a useful drug in combination with cisplatin.

Establishment of Mucoepidermoid Carcinoma Cell Lines from Surgical and Recurrence Biopsy Specimens.

Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC.

Spontaneous Dissection of Left Internal Mammary Artery Graft: A Case Report and Literature Review.

Spontaneous left internal mammary artery (LIMA) graft dissection is a rare condition, and clinical findings remain to be elucidated. We report a case of LIMA graft dissection diagnosed by a coronary computed tomography and intravascular ultrasound. The patient was successfully treated with percutaneous intervention. We also conducted a literature review of published cases and summarized the clinical presentation, pathophysiology, diagnosis, and treatment.

[A Case of De Novo Stage â £ Breast Cancer Successfully Treated with Surgery and Multiple Endocrine Therapies Over a Long Period of Time].

Here we present a case of de novo Stage Ⅳ breast cancer successfully treated with surgery and multiple endocrine therapies over a long period of time. A 75-year-old female presented with a breast tumor with skin invasion and multiple lung metastases. Diagnosed with infiltrating breast cancer of Luminal A-like subtype, endocrine therapy with anastrozole was initiated. Despite initial response to the treatment in both the primary site and lung metastases, the primary tumor regrew and surgery with lumpectomy was performed. After a 3-year-treatment of tamoxifen, axillary lymphadenopathy and bone metastases developed. The patient was treated with fulvestrant for 5 years, resulting in clinical complete response. The now 88-year-old patient has been free of disease without treatment for a year and a half. Generally, primary tumor resection of Stage Ⅳ breast cancer does not improve prognosis, but in this case it provided good local control and enabled long-term endocrine therapy, resulting in prolonged disease-free survival.

[A Case of Primary Gastric Lymphoma with Spontaneous Perforation].

An 85-year-old female patient presented to the emergency department with the chief complaint of sudden upper abdominal pain. The patient suffered from anorexia and epigastric pain for a month, and a local physician suspected a diagnosis of gastric ulcer. An abdominal computed tomography(CT)scan showed intraperitoneal free air as well as irregular thickening and thinning of the gastric wall. Gastric ulcer perforation was suspected, and an emergency operation was performed. Surgical findings showed thickening of the gastric wall in the pylorus and gastric corpus but partial thinning of areas of the anterior wall of the gastric corpus with a perforation measuring 5 mm. A distal gastrectomy and reconstruction were performed using the Billroth Ⅱ method. The histopathological diagnosis was malignant gastric lymphoma(diffuse large B- cell lymphoma). Considering the patient's age and general condition, chemotherapy was not administered after surgery. The patient was alive without recurrence 8 months after the operation.

[Resectable Pancreatic Cancer Successfully Treated with Neoadjuvant Chemotherapy Regimen Change to Modified FOLFIRINOX-A Case Report].

A 72-year-old woman presented with obstructive jaundice. Computed tomography revealed a 12-mm low-density mass in the head of the pancreas. She was diagnosed as having pancreatic cancer by endoscopic ultrasound-guided fine-needle aspiration. She received gemcitabine plus nab-paclitaxel as preoperative chemotherapy. After 2 courses, hepatoduodenal lymph node metastasis appeared and was accompanied by increased tumor marker levels. The regimen was changed to modified FOLFIRINOX. After 5 courses, the lymph node metastasis was reduced in size and the tumor marker levels were decreased, so subtotal stomach-preserving pancreaticoduodenectomy was performed. Adjuvant chemotherapy was administered postoperatively. The patient was alive and well without recurrence 2 years and 9 months after the surgery, but died of sepsis. Nevertheless, this case highlights that when preoperative chemotherapy for resectable pancreatic cancer appears to be ineffective, a change in regimen may be useful.

Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma.

Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4+CD8+ T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4+ CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14-29.0%), enhanced by transforming growth factor-ß1 (TGF-ß1) (mean 29.0-51.2%), and downregulated by trametinib with (mean 51.2-11.4%) or without TGF-ß1 treatment (mean 29.0-6.98%). Phosphorylation of ERK in CD8+ T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.

A rare case of cardiac tumor of the interventricular septum complicated with atrioventricular block.

Lipomatous hypertrophy of the interatrial septum is a rare benign condition characterized by adipocyte hyperplasia with fat infiltration between the myocardial fibers in the interatrial septum. Although lipomatous hypertrophy does not occur only in the interatrial septum, its location in the interventricular septum is extremely rare. A 45-year-old woman with no medical or family history of cardiac disease presented with an episode of syncope. Transthoracic echocardiography revealed an echogenic mass in the interventricular septum and no outflow obstruction. The mass-like area showed fat tissue-specific features on computed tomography and magnetic resonance imaging, and furthermore, it showed late gadolinium enhancement. We diagnosed it as lipomatous hypertrophy of the interventricular septum. An implantable loop recorder documented paroxysmal complete atrioventricular block with presyncope. A permanent dual-chamber pacemaker was implanted. This is the first reported case of lipomatous hypertrophy of the interventricular septum treated with a pacemaker for complete atrioventricular block with syncope. We have described the case and the treatment strategy in detail. Learning objective: To understand lipomatous hypertrophy, a rare disorder, and its characteristics and differences between lipomatous hypertrophy and cardiac adipose tumors on computed tomography and magnetic resonance imaging. To learn about the appropriate treatment and clinical management of this benign condition and treat symptomatic patients.

An In Vivo Study of Local Administration of Low-dose Anti-PD-1 Antibody Using an Oral Cancer Cell Line.

BACKGROUND/AIM: The immunotherapy approach using anti-programmed cell death 1 (PD-1) antibody has been demonstrated in oral cancer treatment. However, serious immune-related adverse events (irAE) have been reported. If local administration of small doses of anti-PD-1 antibody via intraarterial chemoradiotherapy could have the same antitumor effect of systemic administration, this can reduce irAE and medical expenses. In this study, we investigate the antitumor effects of local and systemic administration of a small amount of anti-PD-1 antibody, the overall survival (OS), and the immune environment around cancer. MATERIALS AND METHODS: A mouse buccal mucosal oral squamous cell carcinoma cell line (Sq-1979) was used, and anti-mouse PD-1 was used as the drug. The cell line was transplanted to mouse, and the drug was locally (30 mg/body) and systemically (300 mg/body) administered in a dose. The tumor shrinkage rate and antitumor effect were examined 21 and 29 days after the start of administration. The OS was also compared in each of the groups. Furthermore, the subcutaneous growth of the tumors was inhibited, and the expressions of PD-L1, CD8T cells, perforin, and granzyme B were examined. RESULTS: We found that the local low-dose and systemic groups had the same antitumor effect, OS also showed a significant prolongation. In addition, indicated that the expression of granzyme B was higher in the local low-dose group. CONCLUSION: Local low-dose administration of anti-PD-1 antibody showed the same antitumor effect and OS as systemic normal-dose administration. Therefore, local low-dose administration in oral cancer can be useful.

In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients.

The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.

Tumor-infiltrating FoxP3+ T cells are associated with poor prognosis in oral squamous cell carcinoma.

OBJECTIVES: Squamous cell carcinoma is the most common malignancy in the oral cavity. Moreover, human papillomavirus (HPV) infection has been recently implicated in the onset of oral squamous cell carcinoma (OSCC). Regulatory T cells (Tregs) are Forkhead box P3 (FoxP3) positive and are normally involved in the mechanism by which organisms escape attacks from their own immune system; however, in tumors, these cells are known to suppress antitumor immunity and block the attack against tumors. The present study evaluated the associations of the number of Tregs and HPV infection with prognoses in patients with OSCC. MATERIAL AND METHODS: Samples from 106 patients diagnosed with OSCC were evaluated by immunohistochemical staining for the identification of FoxP3+ Tregs and HPV. The relationship between the observed number of Foxp3-positive cells, the presence/absence of HPV infection and associations with clinicopathological indicators were analyzed. RESULTS: Tissues were classified into high (High) and low (Low) Treg count groups, with 69 patients classified as High and 37 classified as Low. The prognoses were significantly better in the Low group compared with the High group (p = 0.04). FoxP3 expression may have had some effect on nodal metastases (p = 0.09). HPV antigens were detected in 65 patients, but there were no significant associations with prognosis (p = 0.34). HPV-infected tumors were more common in the gums and tongues than in the lips, cheeks, and floor of the mouth (p = 0.05). CONCLUSIONS: These results indicate that Tregs in tumor sites are associated with worsened prognoses of patients with OSCC and suggest potential therapies targeting Tregs in OSCC.

[A Case of Pancreatic Invasive Micropapillary Carcinoma That Survived Seven Years after Resection and Chemotherapy].

We present the case of a 47-year-old man who underwent a subtotal stomach-preserving pancreaticoduodenectomy for pancreatic head cancer. Histopathological diagnosis revealed that the majority of the cancer was an invasive micropapillary carcinoma(IMPC). Postoperative adjuvant chemotherapy using S-1 was continued for 4 years, at the end of which, multiple lymph node metastases were identified. Therefore, gemcitabine plus S-1 therapy was initiated. The treatment reduced the lymph node in size and resulted in the maintenance of a partial response for a year and a half. However, increased lymph node metastases recurred, and multiple lung metastases were noted. The patient died 7 years and 2 months after the resection of the primary lesion. Although pancreatic IMPC has a poor prognosis, long-term survival may be achieved by resection of the primary region, the administration of adjuvant chemotherapy and management of recurrent lesions by chemotherapy.

[Total Pancreatectomy for Remnant Pancreatic Cancer with Positive Washing Cytology after Conversion to Negative Cytology Following Gemcitabine plus Nab-Paclitaxel Therapy-A Case Report].

A 53-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)for resectable pancreatic cancer after neoadjuvant chemotherapy. Postoperatively, she received hepatic arterial infusion of 5-FU and S-1 chemotherapy. Two years after SSPPD, abdominal computed tomography showed a 2-cm mass in the remnant pancreas, which was diagnosed as recurrence of cancer by endoscopic ultrasound-guided fine-needle aspiration. Staging laparoscopy was performed and peritoneal washing cytology(CY)was positive. She then received gemcitabine plus nab-paclitaxel chemotherapy for 8 months. After that, staging laparoscopy was performed again and negative CY was confirmed. A total remnant pancreatectomy with splenectomy was performed. She received chemotherapy after pancreatectomy and is now alive and well without recurrence 2 years and 1 month after the second surgery. Although positive CY is a poor prognostic factor, surgery combined with perioperative chemotherapy may contribute to prolonged survival for some patients who have recurrence in the remnant pancreas with positive CY.

[Locally Advanced HER2-Positive Breast Cancer Successfully Treated with Trastuzumab Emtansine].

Although the prognosis of HER2-positive breast cancer(BC)has been improving than before, that of locally advanced cases is not satisfactory. A 41-year-old female presented with a huge breast lump and massive lymphadenopathy, which was diagnosed as HER2-positive, unresectable, locally advanced BC. The first treatment, consisting of docetaxel, trastuzumab and pertuzumab, had only a limited and temporary effect, with subsequent mass regrowth. After initiation of the second treatment, trastuzumab emtansine(TDM1), the mass gradually shrank, and mastectomy and axillary lymphadenectomy were performed successfully. Histologically, several tiny invasive foci were observed in the mammary gland. No lymph node metastases were observed. The patient subsequently underwent radiation therapy and a 1-year course of TDM1 treatment. The patient has been in remission for 5 years. HER2-positive, locally advanced BC can be successfully treated with multimodal therapy, including anti-HER2 therapy, timely surgery and radiation therapy.

Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab.

Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.