Journal article
A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells
FRONTIERS IN IMMUNOLOGY, v 14, 1157697
30 Mar 2023
PMID: 37063842
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
IntroductionTreatment options for patients with malignant pleural effusions (MPE) are limited due, at least in part, to the unique environment of the pleural space, which drives an aggressive tumor state and governs the behavior of infiltrating immune cells. Modulation of the pleural environment may be a necessary step toward the development of effective treatments. We examine immune checkpoint molecule (ICM) expression on pleural T cells, the secretomes of pleural fluid, pleural infiltrating T cells (PIT), and ability to activate PIT ex vivo. MethodsICM expression was determined on freshly drained and in vitro activated PIT from breast, lung and renal cell cancer. Secretomics (63 analytes) of activated PIT, primary tumor cultures and MPE fluid was determined using Luminex technology. Complementary digital spatial proteomic profiling (42 analytes) of CD45+ MPE cells was done using the Nanostring GeoMx platform. Cytolytic activity was measured against autologous tumor targets. ResultsICM expression was low on freshy isolated PIT; regulatory T cells (T-reg) were not detectable by GeoMx. In vitro activated PIT coexpressed PD-1, LAG-3 and TIGIT but were highly cytotoxic against autologous tumor and uniquely secreted cytokines and chemokines in the > 100 pM range. These included CCL4, CCL3, granzyme B, IL-13, TNF alpha, IL-2 IFN gamma, GM-CSF, and perforin. Activated PIT also secreted high levels of IL-6, IL-8 and sIL-6R alpha, which contribute to polarization of the pleural environment toward wound healing and the epithelial to mesenchymal transition. Addition of IL-6R alpha antagonist to cultures reversed tumor EMT but did not alter PIT activation, cytokine secretion or cytotoxicity. DiscussionDespite the negative environment, immune effector cells are plentiful, persist in MPE in a quiescent state, and are easily activated and expanded in culture. Low expression of ICM on native PIT may explain reported lack of responsiveness to immune checkpoint blockade. The potent cytotoxic activity of activated PIT and a proof-of-concept clinical scale GMP-expansion experiment support their promise as a cellular therapeutic. We expect that a successful approach will require combining cellular therapy with pleural conditioning using immune checkpoint blockers together with inhibitors of upstream master cytokines such as the IL-6/IL-6R axis.
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Details
- Title
- A maladaptive pleural environment suppresses preexisting anti-tumor activity of pleural infiltrating T cells
- Publication Details
- FRONTIERS IN IMMUNOLOGY, v 14, 1157697
- Publisher
- FRONTIERS MEDIA SA; LAUSANNE
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000967639200001
- Scopus ID
- 2-s2.0-85152615252
- Other Identifier
- 991021860723904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology