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Supplementary Methods, Figure Legends from Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer

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posted on 2023-04-03, 21:00 authored by Andrew J. Gunderson, Megan M. Kaneda, Takahiro Tsujikawa, Abraham V. Nguyen, Nesrine I. Affara, Brian Ruffell, Sara Gorjestani, Shannon M. Liudahl, Morgan Truitt, Peter Olson, Grace Kim, Douglas Hanahan, Margaret A. Tempero, Brett Sheppard, Bryan Irving, Betty Y. Chang, Judith A. Varner, Lisa M. Coussens

Supplementary Methods and Figure Legends

Funding

NCI/NIH

Department of Defense Breast Cancer Research Program

the Susan G. Komen Foundation

Lustgarten Foundation

Entertainment Industry Foundation and AACR

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ARTICLE ABSTRACT

Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell–dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ+ tumor–associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a PI3Kγ-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 pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.Significance: We report that BTK regulates B-cell and macrophage-mediated T-cell suppression in pancreas adenocarcinomas. Inhibition of BTK with the FDA-approved inhibitor ibrutinib restores T cell–dependent antitumor immune responses to inhibit PDAC growth and improves responsiveness to chemotherapy, presenting a new therapeutic modality for pancreas cancer. Cancer Discov; 6(3); 270–85. ©2015 AACR.See related commentary by Roghanian et al., p. 230.See related article by Pylayeva-Gupta et al., p. 247.See related article by Lee et al., p. 256.This article is highlighted in the In This Issue feature, p. 217

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    Cancer Discovery

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    Keywords

    Cell CycleSignal transduction pathwaysGastrointestinal CancersPancreatic cancerImmunologyImmune responses to cancerImmunomodulationTumor resistance to immune responseProgression, Invasion & MetastasisInflammation and tumor developmentSmall Molecule AgentsTumor MicroenvironmentTumor-stromal cell interactions

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