Human tissue cultures of lung cancer predict patient susceptibility to immune-checkpoint inhibition

Abstract

Despite novel immunotherapies being approved and established for the treatment of non-small cell lung cancer (NSCLC), ex vivo models predicting individual patients’ responses to immunotherapies are missing. Especially immune modulating therapies with moderate response rates urge for biomarkers and/or assays to determine individual prediction of treatment response and investigate resistance mechanisms. Here, we describe a standardized ex vivo tissue culture model to investigate individual tumor responses. NSCLC tissue cultures preserve morphological characteristics of the baseline tumor specimen for up to 12 days ex vivo and also maintain T-cell function for up to 10 days ex vivo. A semi-automated analysis of proliferating and apoptotic tumor cells was used to evaluate tissue responses to the PD-1 inhibitor nivolumab (n = 12), from which two cases could be successfully correlated to the clinical outcome. T-cell responses upon nivolumab treatment were investigated by flow cytometry and multispectral imaging. Alterations in the frequency of the Treg population and reorganization of tumor tissues could be correlated to nivolumab responsiveness ex vivo. Thus, our findings not only demonstrate the functionality of T cells in NSCLC slice cultures up to 10 days ex vivo, but also suggests this model for stratifying patients for treatment selection and to investigate in depth the tumor-associated T-cell regulation.

In vitroassays for investigating the FLASH effect

“…In addition, the use of patient-derived lung tumour slices can be predictive of the immunotherapy outcome (Ref. 151 ). In summary, tissue slice cultures can be used to study short term radiation effect on the bona fide cellular microenvironment and in physiological conditions.…”

Functional Ex Vivo Tissue-Based Chemotherapy Sensitivity Testing for Breast Cancer

“…In the present paper, we show that this problem can be solved by measuring cell cycle block in mitosis instead of cell death or proliferation parameters. Ex vivo sensitivity assays can be used for various tumor types, such as prostate tumors [ 14 ], lung tumors [ 17 , 18 ] and head-and-neck tumors [ 19 , 20 , 21 ]. Culture media and precise incubation conditions should be optimized for each tumor type and treatment.…”

Complex in vitro model: A transformative model in drug development and precision medicine

“…105 Junk et al fabricated an ex vivo non-small cell lung cancer tissue slice model that maintained the morphological characteristics of tumor specimen for at least 12 days and maintained T-cell function for 10 days in vitro. 108 Further, the tumor-killing effect and T cell responses to nivolumab (a PD-1 antibody) treatment in this model were evaluated, and the results were compared with paired clinical outcomes. The two groups of tissue samples were successfully correlated with their clinical outcomes.…”