Targeting p38-dependent macrophage functions for lung cancer treatment
Pneumology, Thoracic Surgery
Cell Biology
Final Report Abstract
Tumor-associated macrophages (TAMs) play a crucial role during Non-Small Cell Lung Cancer (NSCLC) development. A cross-talk between lung cancer cells and TAMs critically shapes the tumor microenvironment (TME) and immune competency and determines the response to traditional chemotherapy and immunotherapies. TAMs in the tumor niche undergo re-programming by cancer secretome, creating a tumor-supporting local inflammatory environment and suppressing T-cell dependent anti-tumor immunity. With this DFG-funded project, we demonstrated that p38MAPKα is a master regulator of pro-tumorigenic functions of TAMs by controlling M2-polarization and prominent inflammatory, cytokines and metabolic pathways in TAMs. The pathways downregulated by inhibition of p38MAPKα in TAMs mostly represent secreted factors belonging to the kynurenine metabolism, inflammation and cytokine network (15 genes of IFNα,β,γ; 16 interleukins; TNF), Zn and Fe ion metabolism, protein signalling (CXCL12, CCL11, CCL4) and overproduction of IL1RA. Targeting CXCL5, IDO1, ceruloplasmin, an excess of Zn and Fe ions and antagonist of IL1RA anakinra attenuated significantly tumor-promoting features of TAMs. Functions of p38MAPKα in TAMs are very pleiotropic, and potentially either p38MAPK inhibitors (e.g. ralimetinib) or therapeutics targeting one or several of its downstream pathways might be considered as an anti-cancer strategy for NSCLC. We found that p38MAPK gene signature corresponds to TAMs in lung tumors from patients with a worse prognosis or progressive disease. Bioinformatical analysis of clinical data predicted the durable clinical benefit in NSCLC patients in response to anti-PD-1 immunotherapy combined with inhibition of p38MAPK. Presumably, blocking p38MAPK pathways could change the pro-tumor microenvironment in the lungs to one that favors the cytotoxicity of immune cells, particularly via activation of CD4+ Th1 T cells. Complementary treatment of mice with chemotherapy and ralimetinib significantly reduced a tumor load in mice with lung cancer. From the clinical point of view, combining p38MAPK inhibitors with immune- or chemotherapies can potentially improve the outcome of anti-cancer therapy. We also developed biodegradable polymeric multilayer capsules (PMC) to encapsulate small molecule compounds for drug delivery into macrophages in vitro and in vivo in tumor lungs. The designed nano-sized PMC were well retained by lung tumor and efficiently internalized by macrophages in vitro and in vivo. Encapsulated clodronate and ralimetinib blocked TAMs functions. An optimization of PMC shell achieved ≥ 90% uptake efficiency by human primary immune cells ex vivo: macrophages, dendritic cells, T- and NK-cells, Jurkat T cells, mouse primary T cells. PMC and polyplexes can be further optimized to deliver pharmaceuticals or nucleic acids into hard-to-transfect human immune cells ex vivo. Our search for the mechanisms of TAMs functions resulted in assigning active chitinases AMCase and Chit1 as potential macrophage-specific anti-cancer targets. CHIT1 is required for TAMs to support growth of lung cancer cells; high expression of AMCase and CHIT1 correlates with worse overall survival of patients diagnosed with lung adenocarcinoma. Chitinase inhibitors are effective in suppressing lung tumorigenesis; chitinase activity in blood plasma is suitable as a liquid biopsy for NSCLC. In summary, the project led to developing scientific and clinically relevant knowledge on potential approaches for targeting TAMs in lung cancer. The main pool of data is finalized but not yet published.
Publications
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Biodegradable Polymeric Multilayer Capsules for Therapy of Lung Cancer. ACS Applied Materials and Interfaces 12, 5610-5623, 2020
Novoselova M, Loh HM, Trushina D, Ketkar A, Abakumova T, Zatsepin T, Kakran M, Brzozowska A, Hong LH, Gorin D, Antipina M, Brichkina A
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Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy. Cancers. Apr 15;13(8):1908
Koeniger A, Brichkina A, Nee I, Dempwolff L, Hupfer A, Galperin I, Finkernagel F, Nist A, Stiewe T, Adhikary T, Diederich W, Lauth M
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DYRK3 contributes to differentiation and hypoxic control in neuroblastoma. BBRC
Ivanova E, Sharma SD, Brichkina A, Pfefferle P, Keber U, Pagenstecher A, Lauth M
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Matrix stiffness drives autophagy and promotes formation of a stromal metabolic niche. PNAS 118 (40) e2105367118, 2021
Hupfer A, Brichkina A, Koeniger A, Brehm C, Denkert C, Pfefferle P, Helmprobst F, Pagenstecher A, Visekruna A, Lauth A
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The mammalian Hedgehog pathway is modulated by ANP32 proteins. BBRC
Hupfer A, Brichkina A, Adhikari T, Lauth M
