Pancreas ductal adenocarcinoma (PDAC) has one of the worst five-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here we report that targeting Bruton’s Tyrosine Kinase (BTK), a key B cell and macrophage kinase, restores T cell-dependent anti-tumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy (CTX). We report that PDAC tumor growth depends on crosstalk between B cells and FcRγ+ tumor-associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a phosphatidylinositide 3-kinase (PI3K)γ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a TH1 phenotype that fostered CD8+ T cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacological inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.
SUMMARY
The tumor microenvironment plays a critical role in tumor growth, progression, and therapeutic resistance, but interrogating the role of specific tumor-stromal interactions on tumorigenic phenotypes is challenging within
in vivo
tissues. Here, we tested whether three-dimensional (3D) bioprinting could improve
in vitro
models by incorporating multiple cell types into scaffold-free tumor tissues with defined architecture. We generated tumor tissues from distinct subtypes of breast or pancreatic cancer in relevant microenvironments and demonstrate that this technique can model patient-specific tumors by using primary patient tissue. We assess intrinsic, extrinsic, and spatial tumorigenic phenotypes in bioprinted tissues and find that cellular proliferation, extracellular matrix deposition, and cellular migration are altered in response to extrinsic signals or therapies. Together, this work demonstrates that multi-cell-type bioprinted tissues can recapitulate aspects of
in vivo
neoplastic tissues and provide a manipulable system for the interrogation of multiple tumorigenic endpoints in the context of distinct tumor microenvironments.
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