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Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer.

ABSTRACT: Monoacylglycerol lipase (MGL) expressed in cancer cells influences cancer pathogenesis but the role of MGL in the tumor microenvironment (TME) is less known. Using a syngeneic tumor model with KP cells (Kras^LSL-G12D/p53^fl/fl; from mouse lung adenocarcinoma), we investigated whether TME-expressed MGL plays a role in tumor growth of non-small cell lung cancer (NSCLC). In sections of human and experimental NSCLC, MGL was found in tumor cells and various cells of the TME including macrophages and stromal cells. Mice treated with the MGL inhibitor JZL184 as well as MGL knock-out (KO) mice exhibited a lower tumor burden than the controls. The reduction in tumor growth was accompanied by an increased number of CD8⁺ T cells and eosinophils. Naïve CD8⁺ T cells showed a shift toward more effector cells in MGL KOs and an increased expression of granzyme-B and interferon-γ, indicative of enhanced tumoricidal activity. 2-arachidonoyl glycerol (2-AG) was increased in tumors of MGL KO mice, and dose-dependently induced differentiation and migration of CD8⁺ T cells as well as migration and activation of eosinophils in vitro. Our results suggest that next to cancer cell-derived MGL, TME cells expressing MGL are responsible for maintaining a pro-tumorigenic environment in tumors of NSCLC.

SUBMITTER: Kienzl M

PROVIDER: S-EPMC8437460 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer.

Kienzl Melanie M Hasenoehrl Carina C Maitz Kathrin K Sarsembayeva Arailym A Taschler Ulrike U Valadez-Cosmes Paulina P Kindler Oliver O Ristic Dusica D Raftopoulou Sofia S Santiso Ana A Bärnthaler Thomas T Brcic Luka L Hahnefeld Lisa L Gurke Robert R Thomas Dominique D Geisslinger Gerd G Kargl Julia J Schicho Rudolf R

Oncoimmunology 20210911 1

Monoacylglycerol lipase (MGL) expressed in cancer cells influences cancer pathogenesis but the role of MGL in the tumor microenvironment (TME) is less known. Using a syngeneic tumor model with KP cells (Kras<sup>LSL-G12D</sup>/p53<sup>fl/fl</sup>; from mouse lung adenocarcinoma), we investigated whether TME-expressed MGL plays a role in tumor growth of non-small cell lung cancer (NSCLC). In sections of human and experimental NSCLC, MGL was found in tumor cells and various cells of the TME includ ...[more]

PMID: 34527428

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Project description:IntroductionCancer progression is determined not only by the malignant behavior of tumors but also by the immune microenvironment. The tumor immune microenvironment also plays a pivotal role in determining the clinical response of non-small-cell lung cancer (NSCLC) to immunotherapies. To understand the possible mechanisms and explore new targets in lung cancer immunotherapy, we characterized the immune profiles in NSCLC patients.MethodsSeventy-one NSCLC patients who underwent radical resection were selected. The immune cell composition in paired tumor and adjacent normal lung tissues was tested by flow cytometry. The associations of tumor immune microenvironment characteristics with clinicopathological factors and overall survival were analyzed. Kaplan-Meier curves and Cox proportional hazards models were used to determine differences in survival.ResultsCompared with adjacent normal lung tissues, an increased proportion of CD45+ hematopoietic-derived cells, CD4+ T cell subtypes, Tregs and B cells was observed in tumor samples with a reduced frequency of myeloid cell populations. There was no significant increase in total CD8+ T cells, but both PD1+ and CD38+ CD8+ T cells were significantly enriched in tumor samples and statistically significantly associated with tumor size. In addition, positive CD38 expression was highly correlated with PD1 positivity. A high proportion of CD8+ T cells and a low percentage of PD1+ CD8+ T cells were statistically significantly associated with better survival in stage II and III patients, whereas a low frequency of CD38+ CD8+ T cells was statistically significantly associated with better survival in all patients and identified as an independent prognostic factor (p=0.049).ConclusionWe profiled the immune cells in the tumor tissues of NSCLC patients using flow cytometry. The results revealed significant enrichment of infiltrating immune cells. A strong correlation was identified between CD38 and PD-1 expression on CD8+ T cells in tumors. CD8+ T cells and their subtypes play a critical role in the prediction of prognosis.

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Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer.

Publications

Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer.

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