방사선생물학

  • [Cancer Res.] Radiotherapy and CD40 Activation Separately Augment Immunity to Checkpoint Blockade in Cancer.

    University of Pennsylvania / Robert H. Vonderheide*

  • 출처
    Cancer Res.
  • 등재일
    2018 Aug 1
  • 저널이슈번호
    78(15):4282-4291. doi: 10.1158/0008-5472.CAN-17-3821. Epub 2018 May 29
  • 내용

    바로가기  >

    Abstract
    Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell therapy. Mechanisms driving immunosuppression and poor T-cell infiltration in PDA are incompletely understood. Here, we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy and ICB with αCTLA-4 and αPD-1. The combination of an agonist αCD40 antibody, radiotherapy, and dual ICB eradicated irradiated and unirradiated (i.e., abscopal) tumors, generating long-term immunity. Response required T cells and also short-lived myeloid cells and was dependent on the long noncoding RNA myeloid regulator Morrbid Using unbiased random forest machine learning, we built unique, contextual signatures for each therapeutic component, revealing that (i) radiotherapy triggers an early proinflammatory stimulus, ablating existing intratumoral T cells and upregulating MHC class I and CD86 on antigen-presenting cells, (ii) αCD40 causes a systemic and intratumoral reorganization of the myeloid compartment, and (iii) ICB increases intratumoral T-cell infiltration and improves the CD8 T-cell:regulatory T-cell ratio. Thus, αCD40 and radiotherapy nonredundantly augment antitumor immunity in PDA, which is otherwise refractory to ICB, providing a clear rationale for clinical evaluation.Significance: Radiotherapy and αCD40 disrupt key links between innate and adaptive immunity, ameliorating resistance to immune checkpoint blockade in pancreatic cancer via multiple cellular mechanisms.

     


    Author information

    Rech AJ1, Dada H2, Kotzin JJ3,4, Henao-Mejia J3,4,5, Minn AJ1,4,6,7, Twyman-Saint Victor C#2,4,6,7, Vonderheide RH#8,2,4,7.
    1
    Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
    2
    Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    3
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    4
    Institute for Immunology, University of Pennsylvania, Philadelphia, Pennsylvania.
    5
    Division of Transplant Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
    6
    Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    7
    Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
    8
    Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. rhv@upenn.edu.
    #
    Contributed equally

  • 덧글달기
    덧글달기
       IP : 44.192.253.106

    등록