Immunotherapy response modeling by ex-vivo organ culture for lung cancer

Iris Kamer, Elizabeta Bab-Dinitz, Oranit Zadok, Efrat Ofek, Teodor Gottfried, Inbal Daniel-Meshulam, Goni Hout-Siloni, Alon Ben Nun, Iris Barshack, Amir Onn, Jair Bar

    Research output: Contribution to journalArticlepeer-review

    10 Scopus citations

    Abstract

    One of the major hurdles for the advancement of cancer immunotherapy is lack of robust, accessible experimental models. We aimed to produce an ex-vivo organ culture (EVOC) model of immunotherapy for non-small cell lung cancer (NSCLC). Freshly resected early stage tumors were collected from the operating room, fragmented to clusters < 450 µm and cultured with fetal calf serum and human autologous serum. The resulting EVOC includes cancer epithelial cells within tumor tissue clusters and immune cells. Original tissue features are reflected in the EVOCs. The response to immune checkpoint inhibitors (ICI) was assessed by IFNγ gene induction. Interestingly, IFNγ EVOC induction was numerically higher when anti-CTLA4 was added to anti-PD-L1 treatment, supporting the notion that anti-CTLA4 impacts cancer partly through tumor-resident immune cells. In parallel, immunohistochemistry (IHC) for key immune-related proteins was performed on the formalin-fixed paraffin embedded (FFPE) corresponding tumors. EVOC IFNγ induction by ICI correlated with basal non-induced IFNγ, CD8, CD4 and FOXP3 mRNA levels within EVOCs and with tumor-FFPE-IHC for CD8 and granzyme B. A weaker correlation was seen with tumor-FFPE-IHC for CD3, CD4, CD68, FOXP3 and tumor-PD-L1. Tertiary lymphoid structure density was also correlated with the ICI response. Our study provides novel data about biomarkers that correlate with ICI-induced response of early stage NSCLC. Retention of the microenvironment and minimal addition of exogenous factors suggest this model to reliably represent the original tumor. The cluster-based EVOC model we describe can provide a valuable, yet simple and widely applicable tool for the study of immunotherapy in NSCLC.

    Original languageEnglish
    Pages (from-to)2223-2234
    Number of pages12
    JournalCancer Immunology, Immunotherapy
    Volume70
    Issue number8
    DOIs
    StatePublished - 1 Aug 2021

    Keywords

    • Anti-CTLA4
    • Anti-PD-L1
    • Early-stage NSCLC
    • IFNγ
    • Tumor-microenvironment

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Oncology
    • Cancer Research

    Fingerprint

    Dive into the research topics of 'Immunotherapy response modeling by ex-vivo organ culture for lung cancer'. Together they form a unique fingerprint.

    Cite this