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Theranostics 2022; 12(1):167-185. doi:10.7150/thno.61209 This issue Cite

Research Paper

Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma

Haitang Yang1,2,3, Sabina Berezowska4*, Patrick Dorn1, Philipp Zens4,5, Peiru Chen6, Ren-Wang Peng1,2, Thomas M. Marti1,2, Gregor J Kocher1,2, Ralph A. Schmid1,2✉, Sean R.R. Hall1,2#✉

1. Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland.
2. Department of BioMedical Research, University of Bern, Bern, Switzerland.
3. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
4. Institute of Pathology, University of Bern, Bern, Switzerland.
5. Graduate School for Health and Sciences, University of Bern, Switzerland.
6. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, People's Republic of China.
* Present address: Institute of Pathology, Lausanne University Hospital and University of Lausanne, Bugnon 25, 1011 Lausanne, Switzerland.
# Present address: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

✉ Corresponding authors: Sean Hall PhD or Ralph A. Schmid MD, 1Division of General Thoracic Surgery, Inselspital, Bern University Hospital and 2Department of BioMedical Research, University of Bern, Murtenstrasse 50, 3008 Bern, Switzerland. Tel. +41 0 More

Citation:
Yang H, Berezowska S, Dorn P, Zens P, Chen P, Peng RW, Marti TM, Kocher GJ, Schmid RA, Hall SRR. Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma. Theranostics 2022; 12(1):167-185. doi:10.7150/thno.61209. https://www.thno.org/v12p0167.htm
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Abstract

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Rationale: Despite evidence suggesting that the tumor microenvironment (TME) in malignant pleural mesothelioma (MPM) is linked with poor prognosis, there is a lack of studies that functionally characterize stromal cells and tumor-infiltrating lymphocytes (TILs). Here, we aim to characterize the stromal subsets within MPM, investigate their relationship to TILs, and explore the potential therapeutic targets.

Methods: We curated a core set of genes defining stromal/immune signatures expressed by mesenchymal cells within the TME using molecular analysis of The Cancer Genome Atlas (TCGA) MPM cohort. Stromal and immune profiles were molecularly characterized using flow cytometry, immunohistochemistry, microarray, and functionally evaluated using T cell-activation/expansion, coculture assays and drug compounds treatment, based on samples from an independent MPM cohort.

Results: We found that a high extracellular matrix (ECM)/stromal gene signature, a high ECM score, or the ratio of ECM to an immune activation gene signature are significantly associated with poor survival in the MPM cohort in TCGA. Analysis of an independent MPM cohort (n = 12) revealed that CD8+ and CD4+ TILs were characterized by PD1 overexpression and concomitant downregulation in degranulation and CD127. This coincided with an increase in CD90+ cells that overexpressed PD-L1 and were enriched for ECM/stromal genes, activated PI3K-mTOR signaling and suppressed T cells. Protein array data demonstrated that MPM samples with high PD-L1 expression were most associated with activation of the mTOR pathway. Further, to reactivate functionally indolent TILs, we reprogrammed ex vivo TILs with Ibrutinib plus Rapamycin to block interleukin-2-inducible kinase (ITK) and mTOR pathways, respectively. The combination treatment shifted effector memory (TEM) CD8+ and CD4+ TILs towards T cells that re-expressed CD45RA (TEMRA) while concomitantly downregulating exhaustion markers. Gene expression analysis confirmed that Ibrutinib plus Rapamycin downregulated coinhibitory and T cell signature pathways while upregulating pathways involved in DNA damage and repair and immune cell adhesion and migration.

Conclusions: Our results suggest that targeting the TME may represent a novel strategy to redirect the fate of endogenous TILs with the goal of restoring anti-tumor immunity and control of tumor growth in MPM.

Keywords: malignant pleural mesothelioma, tumor microenvironment, tumor-infiltrating lymphocytes, exhaustion, reprogram

Citation styles

APA
Yang, H., Berezowska, S., Dorn, P., Zens, P., Chen, P., Peng, R.W., Marti, T.M., Kocher, G.J., Schmid, R.A., Hall, S.R.R. (2022). Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma. Theranostics, 12(1), 167-185. https://doi.org/10.7150/thno.61209.

ACS
Yang, H.; Berezowska, S.; Dorn, P.; Zens, P.; Chen, P.; Peng, R.W.; Marti, T.M.; Kocher, G.J.; Schmid, R.A.; Hall, S.R.R. Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma. Theranostics 2022, 12 (1), 167-185. DOI: 10.7150/thno.61209.

NLM
Yang H, Berezowska S, Dorn P, Zens P, Chen P, Peng RW, Marti TM, Kocher GJ, Schmid RA, Hall SRR. Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma. Theranostics 2022; 12(1):167-185. doi:10.7150/thno.61209. https://www.thno.org/v12p0167.htm

CSE
Yang H, Berezowska S, Dorn P, Zens P, Chen P, Peng RW, Marti TM, Kocher GJ, Schmid RA, Hall SRR. 2022. Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma. Theranostics. 12(1):167-185.

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