Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy.

New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Total as well as tumor antigen-specific CD8+ T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. Cancer Immunol Res; 5(7); 535-46. ©2017 AACR.

Dammeijer F ，Lievense LA ，Kaijen-Lambers ME ，van Nimwegen M ，Bezemer K ，Hegmans JP ，van Hall T ，Hendriks RW ，Aerts JG ... -  《-》

Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS.

de Goeje PL ，Klaver Y ，Kaijen-Lambers MEH ，Langerak AW ，Vroman H ，Kunert A ，Lamers CHJ ，Aerts JGJV ，Debets R ，Hendriks RW ... -  《Frontiers in Immunology》

Antigen spreading-induced CD8+T cells confer protection against the lethal challenge of wild-type malignant mesothelioma by eliminating myeloid-derived suppressor cells.

Yu Z ，Tan Z ，Lee BK ，Tang J ，Wu X ，Cheung KW ，Lo NT ，Man K ，Liu L ，Chen Z ... -  《-》

Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma.

Jassar AS ，Suzuki E ，Kapoor V ，Sun J ，Silverberg MB ，Cheung L ，Burdick MD ，Strieter RM ，Ching LM ，Kaiser LR ，Albelda SM ... -  《CANCER RESEARCH》

A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma.

Yuan J ，Kashiwagi S ，Reeves P ，Nezivar J ，Yang Y ，Arrifin NH ，Nguyen M ，Jean-Mary G ，Tong X ，Uppal P ，Korochkina S ，Forbes B ，Chen T ，Righi E ，Bronson R ，Chen H ，Orsulic S ，Brauns T ，Leblanc P ，Scholler N ，Dranoff G ，Gelfand J ，Poznansky MC ... -  《Journal of Hematology & Oncology》