824 Modulation of TLR3 protein in response to radiation in squamous cell lung carcinoma

BackgroundSquamous cell lung cancer (SCLC) is the second most common type of lung cancer. Treatment is complicated due to the lack of mutated molecular targets.1 Radiotherapy (RT) is commonly used to treat SCLC, but relapse and tumor progression are common. The combination of immunotherapy (IT) with RT can enhance the effect observed with RT alone.2 Effective combination of IT and RT requires an understanding of the pathways that synergize to enhance tumor cell kill in SCLC. Our lab has identified Toll-like receptor 3 (TLR3) as a molecule that is regulated by RT and can be targeted with IT. Toll-like receptors serve a crucial role against tumor cells by activating innate and adaptive immune responses that boost antitumor immunity.3 4 TLR3 is the only receptor whose molecular mechanism functions independent of MyD88, leading to NF-κB mediated apoptosis.5 We hypothesized that increased TLR3 expression would be associated with improved response to RT. We further hypothesized that RT can downregulate TLR3 and that this effect can be reversed with TLR3 agonists leading to enhanced tumor antigen recognition. We aim to use this data to formulate further studies using combined RT and IT.MethodsMouse (KLN205) and human (SW900) squamous cell carcinoma (SCC) cell lines were used to study the effect of radiation on TLR3 expression. Irradiation was performed using the gammacell 3000 elan irradiator. Cells were irradiated with 0, 5, 10 and 20 Gy. Protein extraction was performed 48 and 72 hours after RT. Protein extracts were analyzed by Western Blot. Further, TLR3 mRNA expression and 5-year overall survival of SCLC patients was obtained from public databases. Kaplan-Meier method was used to correlate between TLR3 mRNA expression and survival.ResultsIn vitro studies and western blot analysis demonstrated a decrease of TLR3 expression in response to increasing doses of radiation. This observation was consistent in mouse and human SCC cell lines. In silico analysis of SCLC patients who received RT showed that increased TLR3 mRNA expression was associated with improved overall survival and disease-free survival.ConclusionsOur findings point to an important role for TLR3 in SCLC. Combining RT with TLR3 agonists may enhance the tumor response to RT. Several complementary experiments are underway in our lab to use the TLR3 agonist, Poly I:C, which will allow a better understanding of the effect of RT on TLR3.ReferencesGeorge J, Lim SJ, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47–53.Darragh L, Oweida A, Karam SD. Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways withing the tumor microenvironment. Frontiers in Immunology 2019;9:3154.Shcheblyakov D, Logunov DY, Tukhvatulin AI, et al. Toll-Like Receptors (TLRs): The Role in Tumor Progression. Acta Naturae 2010;2(3):21-9.Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010;11:373–384.Bianchi F, Alexiadis S, Camiasaschi C, et al. TLR3 expression induces apoptosis in Human Non-Small-Cell Lung Cancer. Int J Mol Sci 2020 Feb;21(4):1440.

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The Overall Survival of Non-Small Cell Lung Cancer Patients Group pN2 after Radical Surgery and Postoperative Radiotherapy

Medical Radiology and radiation safety ◽

10.12737/1024-6177-2020-65-1-42-47 ◽

2020 ◽

Vol 65 (1) ◽

pp. 42-47

Author(s):

V. Sotnikov ◽

G. Panshin ◽

V. Solodkiy ◽

V. Chkhikvadze ◽

V. Kharchenko ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Squamous Cell Carcinoma ◽

Small Cell Lung Cancer ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cell Lung Cancer ◽

Postoperative Radiotherapy ◽

Small Cell ◽

Small Cell Lung

Purpose: Comparative analysis of the overall survival (OS) in different subgroups of the patients with non-small cell lung cancer (NSCLC) with affected mediastinal lymph nodes (pN2) after surgical and combined treatment using postoperative radiotherapy (PORT). Material and methods: A comparative assessment of the overall survival of 243 patients with NSCLC stages IIIA, IIIB (pT1–4N2M0) was carried out: the I group – 79 patients after radical (R0) surgical treatment (lobe/bilobectomy, pulmonectomy with ipsilateral mediastinal lymph node dissection) and the second group – 164 patients after the combined modality therapy with the same volume of surgery and postoperative radiotherapy in the mode of hypofractionation (daily dose 3 Gy, 5 times a week, TD = 36–39 Gy (EQD2 = 43.2–46.8 Gy, α/β = 3) or classical fractionation (2 Gy, 5 times a week, TD = 44 Gy). We analyzed subgroups of men and women, patients younger than 60 years and older, with central and peripheral cancer, squamous cell carcinoma and adenocarcinoma, with different gradation of tumors according to the criterion T (pT1–4). Results: In the compared groups, 2-year and 5-year OS was significantly higher in the PORT group (62.4 and 31.6 vs 44.8 % and 12.3 %, p = 0.0028), at the expense of male patients (62.4 and 31.6 % vs 44.8 and 12.3 %, p = 0.0028), patients with central cancer (59.2 and 43.7 % vs 36.3 % and n/a, p = 0.0023), patients with squamous cell carcinoma (64.0 % and 43.1 % vs 42.3 % and 6.7 %, p = 0.0006), patients older than 60 years (74.8 and 46.2 % vs 45.1 % and n/a, p = 0.007). A more detailed analysis revealed that PORT significantly increased 2- and 5-year OS in the central squamous cell carcinoma of the lung (67.3 and 53.0 % vs. 33.3 and 0 %, respectively, p = 0.0013), and in pT3–4 tumors (2-year OS 57.1 vs. 36.4 %, respectively, p = 0.0102). There was only a tendency of increasing OS after the PORT in T2 tumors (5-year OS 31.1 vs 15.4 %, respectively, p = 0.1319). In T1 tumors, no differences in OS were found, possibly due to the small number of cases (27). In peripheral squamous cell carcinoma there was a statistically insignificant increasing of 5-year OS – 7 %. There was no significant differences in OS survival were obtained in central and peripheral lung adenocarcinoma between the I and II groups. Conclusion: In the patients with non-small cell lung cancer pN2, radically operated (R0) in the volume of lobe/bilobectomy, pulmonectomy with ipsilateral mediastinal lymph node dissection, PORT can be recommended for central squamous cell carcinoma pT1–4. In the patients with peripheral squamous cell carcinoma, PORT can be discussed for the patients with individually assessed high risk of the locoregional relapse. PORT, within the scope of irradiation and total doses used in this study, has no age restrictions. The feasibility of PORT for radically operated patients with pN2 lung adenocarcinoma requires further study.

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Association of tumor-specific GPR87 overexpression with poor prognosis in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22108 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22108-e22108

Author(s):

Kazuhito Nii ◽

Dage Liu ◽

Yoshimasa Tokunaga ◽

Xia Zhang ◽

Shinya Ishikawa ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Squamous Cell ◽

Cell Lung Cancer ◽

Human Tumor ◽

Small Cell ◽

Proliferation Index ◽

Small Cell Lung ◽

Ki 67

e22108 Background: GPR87 is a member of G-protein-coupled receptors (GPCRs). Recently, GPR87 was suggested to contribute to the viability of human tumor cells, and the overexpression of GPR87 mRNA was found in many malignant tumors including lung cancer. However, the clinical significance of GPR87 expression in non-small cell lung cancer (NSCLC) has not been well studied. Methods: 127 NSCLC patients who underwent surgery from 1999 to 2004 were investigated. There were 59 adenocarcinomas, 55 squamous cell carcinomas and 13 others. The intratumoral expression of GPR87 was evaluated by immunohistochemistry. The Ki-67 proliferation index was also evaluated. Results: A tumor-specific expression of GPR87 was found in NSCLC in comparison with the surrounding normal tissue. Fifty-nine tumors (46.5%) were found to be high-GPR87 tumors. The high-GPR87 tumors were more frequently found in squamous cell carcinoma than in adenocarcinoma (60.0% versus 37.3%, p=0.02). Regarding the tumor proliferation, the Ki-67 index was significantly higher in high-GPR87 tumors than in low-GPR87 tumors (p=0.04). There was a tendency that the overall survival was worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.22). For the patients with adenocarcinoma, the overall survival was significantly worse in patients with high-GPR87 tumors than in low-GPR87 tumors (p=0.04). Conclusions: GPR87 expression may become a poor prognostic predictor for patient with NSCLC, especially for those with adenocarcinoma. GPR87 may contribute to the cell viability by promoting cell proliferation, has a potential to become a novel therapeutic target for cancer treatment.

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Evaluation on the role of ERCC1, RRM1 and TUBB3 mRNA expression on the tumor response and overall survival of non-small cell lung cancer treated with platinum-based chemotherapy

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.306.5768 ◽

1969 ◽

Vol 30 (6) ◽

Author(s):

Xingyi Zhang

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Mrna Expression ◽

Cell Lung Cancer ◽

Tumor Response ◽

Small Cell ◽

Small Cell Lung ◽

Platinum Based Chemotherapy

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Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients

Journal of Translational Medicine ◽

10.1186/s12967-020-02618-z ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Ilseon Hwang ◽

Jeong Won Kim ◽

Kris Ylaya ◽

Eun Joo Chung ◽

Haruhisa Kitano ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Tumor Progression ◽

Mrna Expression ◽

Cell Lung Cancer ◽

A549 Cells ◽

Small Cell ◽

Small Cell Lung ◽

Poor Overall Survival

Abstract Background The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME and generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical, angiogenic, and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC). Methods Utilizing combined immunohistochemistry and digital image analysis, we assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC. Subsequently, the potential association between M2 TAMs and angiogenic VEGF-A and/or lymphangiogenic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored via an in vitro co-culture system. Results CD68 and CD163 expression were found to directly correlate with VEGF-A and/or VEGF-C expression (all p < 0.001). Furthermore, elevated M2 ratio (CD163+/CD68+) was significantly associated with poor overall survival (p = 0.023). Dual expression of M2 ratiohigh and VEGF-Chigh (M2 ratiohighVEGF-Chigh) was correlated with worse overall survival (p = 0.033). Multivariate analysis revealed that M2 ratiohigh [HR (95% CI) = 1.53 (1.01–2.33), p = 0.046] and combined M2 ratiohighVEGF-Chigh expression [HR (95% CI) = 2.01 (1.28–3.16), p = 0.003] were independent predictors of poor overall survival. Notably, we confirmed that M2 macrophages significantly enhanced the protein and mRNA expression of both VEGF-A and VEGF-C, while M1 macrophages induced only mRNA expression of VEGF-A in A549 cells. Conclusions This study suggests that TAMs are significantly associated with angiogenesis and lymphangiogenesis, contributing to the progression of NSCLC. Furthermore, elevated M2 ratio, similar to combined high M2 ratio and high VEGF-C expression, is a strong indicator of poor prognosis in patients with NSCLC, providing insight for future TAM-based immunotherapy strategies.

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