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

David Junk,Florian Lordick,Johannes Broschewitz,Barbara Seliger,Astrid Monecke,Yousef Moulla,Ingo Bechmann,Chiara Massa,Hennig Laura,Ngoc Anh Hoang,Sebastian Krämer,Sonja Kallendrusch,Uwe Eichfeld

doi:10.1038/s41420-021-00651-5

David Junk, Florian Lordick + Show 11 more

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https://doi.org/10.1038/s41420-021-00651-5

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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.

Highlights

non-small cell lung cancer (NSCLC) is responsible for the most cancer-related deaths worldwide and has the highest incidence rate among all tumors [1]
In the presence of genetic mutations (EGFR, ALK), patients benefit from treatment with selective EGFR inhibitors or the ALK inhibitor crizotinib compared to standard chemotherapy for NSCLC tumors [3, 4]
The pathological diagnosis of the original tumor matched the features found in baseline culture, representatively shown in Table 1. 4/24 cases (16,6%) were excluded from the analysis due to high necrotic areas and inflammatory regions observed in the baseline tissue

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Introduction

NSCLC is responsible for the most cancer-related deaths worldwide and has the highest incidence rate among all tumors [1]. Two main histological subtypes classify the NSCLC, the squamous NSCLC (sNSCLC) and the NSCL adenocarcinoma (NSCLaC). Several molecular subtypes of this disease are identified. High mutation loads, and late diagnosis are some major factors responsible for the poor prognosis of patients, with a 5 years’ survival rate of ~17% [2]. In the presence of genetic mutations (EGFR, ALK), patients benefit from treatment with selective EGFR inhibitors (e.g., gefitinib and erlotinib) or the ALK inhibitor crizotinib compared to standard chemotherapy for NSCLC tumors [3, 4]. Only very few patients are eligible for targeted therapy, examining the mutational burden or other specific predictive markers [5]

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