Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response

Floris Dammeijer*, CJ Gooijer, Mandy van Gulijk, Melanie Lukkes, Larissa Klaase, Sanne Lievense, Cynthia Waasdorp, M Jebbink, GP Bootsma, JA Stigt, B Biesma, Margaretha Lambers, Joanne Mankor, Heleen Vroman, Robin Cornelissen, P Baas, V van der Noort, JA Burgers, Joachim Aerts

*Corresponding author for this work

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Abstract

Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.

Original languageEnglish
Article number103160
JournalEBioMedicine
Volume64
DOIs
Publication statusPublished - 1 Feb 2021

Bibliographical note

Funding Information:
We thank the members of the NVALT19 Study Team for their many contributions in conducting the trial. We thank The Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding (KWF) and The Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NVALT) Study Group for the funding support. Funding: Dutch Cancer Society (KWF Kankerbestrijding) and the NVALT Study Group.

Funding Information:
We thank the members of the NVALT19 Study Team for their many contributions in conducting the trial. We thank The Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding (KWF) and The Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NVALT) Study Group for the funding support.

Funding Information:
JGA reports personal fees and non-financial support from MSD, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from amphera, personal fees from Eli-Lilly, personal fees from Takeda, personal fees from Bayer, personal fees from Roche, personal fees from Astra Zeneca, all outside the submitted work; In addition, JGA has a patent on allogenic tumour cell lysate licensed to amphora (EP2938354A1), a patent combination immunotherapy in cancer (pending), and a patent biomarker for immunotherapy (pending) . PB participated in advisory boards of MSD and BMS and AstraZeneca for which the Netherlands Cancer Institute received a reimbursement, outside the submitted work. PB participated in advisory boards of Takeda. PB received financial support for an investigator-initiated trial from MSD and BMS. RC participated in advisory boards of MSD and Roche and received a speaker fee from Roche, Pfizer and BMS, outside the submitted work. JAB reports reimbursement from BMS and F Hoffmann-La Roche for the Netherlands Cancer Institute, and financial support for an investigator-initiated trial from MSD, outside the submitted work. CJG, VN, JS, FD, BB, GB, MJ, LK, JM, LL, CW, MVG, HV, MKL and ML declare no competing interests.

Publisher Copyright:
© 2020 The Authors

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