Introduction: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC).Methods: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung eld (P-AMs), and in the lung eld distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage uid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n=3).Results: Patients with high P-AMs had signi cantly shorter overall survival (OS) (p<0.01); however, patients with high D-AMs did not have signi cantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a signi cantly shorter OS (p<0.01). In multivariate analysis, a higher number of P-AMs was an independent poor prognostic factor (p=0.02). Ex vivoBALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung elds in all 3 cases (IL-10: 2.2, 3.0, and 10.0-fold; CCL-2: 3.0, 3.1, and 3.2-fold). Moreover, addition of recombinant CCL2 signi cantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. Conclusion:The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of peritumoral tumor microenvironment in lung SqCC progression.
The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10-2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment.
Background: CLIP1-LTK was recently discovered as a novel oncogenic gene fusion in non-small cell lung cancer (NSCLC). Lorlatinib, an ALK/ROS1 inhibitor, can inhibit CLIP1-LTK constitutive kinase activity, and showed dramatic and promising efficacy in a patient with NSCLC harboring CLIP1-LTK fusion. However, acquired resistance to lorlatinib will be inevitably developed, especially by mutations in LTK gene, as 50-60% of oncogenic driver-positive NSCLC develop resistance to kinase inhibitors by acquired mutations in the target gene. The aim of this study is to identify the LTK mutations responsible for resistance to lorlatinib in CLIP1-LTK fusion positive NSCLC, and to explore compounds that can overcome resistance. Methods: As LTK and ALK share nearly 80% protein sequence identity in their respective kinase domains, we established Ba/F3 cells expressing CLIP1-LTK (Ba/F3-CLIP1-LTK) with six different LTK mutations (I565N, F568C, L590M, L592F, G596R, and G663A), all of which are analogous to reported ALK mutations responsible for resistance to lorlatinib. Ba/F3 cells expressing CLIP1-LTK with these different LTK mutations, as well as CLIP1-LTK-wild type (WT) were treated with several concentrations of lorlatinib. Then, the efficacy of other compounds including crizotinib, alectinib, ceritinib, brigatinib, entrectinib, giltertinib, repotorectinib was assessed to detect which compounds can overcome lorlatinib resistance. Results: All LTK mutations tested showed resistance to lorlatinib, with IC50s of lorlatinib ranging 2.7 to 31.3 nM, which were higher than that in Ba/F3-CLIP-LTK-WT (1.0 nM) in cell viability assay. An IC50 of giltertinib in Ba/F3-CLIP1-LTK-F568C was lower than that of lorlatinib (0.9 vs 2.7 nM). Moreover, an IC50 of giltertinib in Ba/F3-CLIP1-LTK-G663A was lower than that of lorlatinib (2.7 vs 19.4 nM). Ba/F3-CLIP1-LTK-L592F was rather sensitive to crizotinib compared with Ba/F3-CLIP1-LTK-WT (IC50, <0.1 vs 16.5 nM). Similarly, Ba/F3-CLIP1-LTK-G596R was similar to repotorectinib compared with WT (IC50, 10.4 vs 11.3 nM). The results of western blotting assay evaluating phosphorylation of CLIP1-LTK were in accordance with that obtained cell viability assay. Conclusion: We identified that several LTK mutations, analogous to ALK resistant mutations, were responsible for lorlatinib resistance, some of which can be overcome by existing compounds. Further validation and exploration are warranted to establish resistance mechanism-based precision medicine following lorlatinib treatment in CLIP1-LTK fusion-positive NSCLC. Citation Format: Shunta Mori, Hiroki Izumi, Jie Liu, Kosuke Tanaka, Shogo Kumagai, Takuma Hayashida, Yosuke Kagawa, Yuji Shibata, Shingo Matumoto, Koichi Goto, Susumu Kobayashi. LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5351.
Introduction: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC). Methods: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs), and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFβ, and TNFα (n=3). Results: Patients with high P-AMs had significantly shorter overall survival (OS) (p<0.01); however, patients with high D-AMs did not have significantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a significantly shorter OS (p<0.01). In multivariate analysis, a higher number of P-AMs was an independent poor prognostic factor (p=0.02). Ex vivoBALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2, 3.0, and 10.0-fold; CCL-2: 3.0, 3.1, and 3.2-fold). Moreover, addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. Conclusion: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of peritumoral tumor microenvironment in lung SqCC progression.
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