Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti‐human podoplanin mAb, NZ‐1, and a rat–human chimeric anti‐human podoplanin antibody, NZ‐8, derived from NZ‐1, which induced antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity against podoplanin‐positive MPM cell lines. In this study, we showed the antitumor effect of NZ‐1, NZ‐8, and NZ‐12, a novel rat–human chimeric anti‐human podoplanin antibody derived from NZ‐1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ‐1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI‐H290/PDPN or NCI‐H226 orthotopic xenograft mouse models. NZ‐8 and human natural killer (NK) (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ‐12 induced potent ADCC mediated by human MNC, compared with either NZ‐1 or NZ‐8. Antitumor effects were observed following treatment with NZ‐12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ‐12 mediated by human NK (CD56+) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin‐targeting immunotherapy using both NZ‐12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8 + T cells by fibrocytes was examined in MLRs with a 3 Hthymidine incorporation assay. Fibrocytes expressed CD80 low and CD86 high as a costimulatory molecule, and expressed PD-L1 high , but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8 + T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8 + T cells induced by fibrocytes. Anti-PD-L1 Ab further enhanced the proliferation of CD8 + T cells, even in the OVA-specific MLR with OT-1Rag 2/2 mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8 + T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8 + T cells when the activity is further enhanced by PD-L1/PD-1 blockade.

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Small-cell lung cancer (SCLC) accounts for 15 -20% of lung cancer (1) and presents aggressive clinical behavior characterized by rapid growth, metastatic spread to the distant organs (2). Despite the high response rate to initial chemotherapy, most patients subsequently experience a relapse of the primary tumor or distant metastasis, and the prognosis is still poor. SCLC is clinically categorized as two stages, limited disease (LD) and extensive disease (ED). LD-SCLC is defined as to be confined to the ipsilateral hemithorax and regional nodes, and able to be included in a single tolerable radiotherapy port. LD-SCLC is primarily treated with a combination of chemotherapy and radiotherapy, and its prognosis is improved by the development novel effective radiation therapy, such as accelerated hyperfractionated thoracic radiotherapy (AHF-TRT) (3). On the other hands, for ED-SCLC which is beyond the boundaries of LD including distant metastases, malignant pericardial, or pleural effusion and contralateral supraclavicular and contralateral hilar involvement, platinum-based combination chemotherapy alone is used as the initial therapy (4 -6). Despite the several novel anticancer agents against non-small cell lung cancer were developed and shown to have favorable outcome, the chemotherapy regimens against SCLC were not making any progress in recent decade, which leads to the poor prognosis of ED-SCLC.In the past, several studies were performed to reveal the prognostic factors in SCLC (7 -19). In these studies, male, poor performance status (PS) and weight loss as the host factors, and the extent of disease, number of metastatic sites, brain metastasis, bone metastasis, liver metastasis, elevated white blood cell (WBC) counts, neutrophil counts, serum lactate dehydrogenase (LDH), alkaline phosphatase (ALP), decreased platelet (PLT) counts, albumin (ALB), sodium, and C -reactive protein (CRP) as the tumor -related factors were reported to be unfavorable prognostic factors in multivariate analysis. Among these factors, existence of distant organ metastasis become easily a major problem of treatment in clinics, and metastatic involvement of the central nervous system, the bone marrow, or the liver is usually unfavorable compared with other sites.For the brain metastasis of SCLC, whole brain radiotherapy (WBRT) was mainly performed currently in the combination with chemotherapy. Moreover, novel stereotactic irradiation (STI) techniques were developed recently, such as stereotactic radiosurgery (SRS) or volumetric-modulated arc therapy (VMAT), resulted in improving the management of adverse events and prognosis (20 -23). For the bone metastasis, not only palliative radiotherapy (24), but also novel bone modifying agents (BMAs), such as zoledronic acid or denosumab can be used in recent days (25)(26). On the other hands, we still have few treatment strategies against liver metastasis, and frequently faced lethal clinical courses of aggressive and uncontrollable liver metastasis.Given that most of data regarding the prognostic...