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María José Pajares
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.06 - Prognostic Value of Complement System in NSCLC and its Association with PD-1 and PD-L1 Expression (ID 12372)
11:05 - 11:10 | Author(s): María José Pajares
- Abstract
- Presentation
Background
Recent research has unveiled novel molecular mechanisms linking imbalanced complement activation and cancer progression. In this context, complement inhibition has emerged as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint.
a9ded1e5ce5d75814730bb4caaf49419 Method
Lung cancer tissues were obtained from 140 patients treated by surgery at the Clinica Universidad de Navarra. Inclusion criteria were: NSCLC histology, complete resection of the primary tumor, absence of cancer within the five years previous to the lung cancer surgery, and no treatment with chemo- or radiotherapy prior to surgery. Resected primary lung tumors were fixed in formalin and embedded in paraffin. After antigen retrieval samples were incubated with anti-human C4d, C5aR1, C1q, PD-1 and anti-PD-L1 followed by detection with the Envision system (Dako). Peroxidase activity was visualized with 3,3’-diaminobenzidine. Sections were slightly counterstained with hematoxylin. Two independent and blinded observers calculated an H -score based on intensity and extension of the staining. Survival curves were generated using the Kaplan–Meier method, and statistically significant differences were analyzed with the log rank test.
4c3880bb027f159e801041b1021e88e8 Result
Immunohistochemistry of complement proteins in NSCLC was performed for C1q, the target recognition of the complement pathway in NSCLC, C4d, a split product of complement activation, and C5aR1, the complement C5a anaphylatoxin receptor. Immunohistochemical analysis showed positive staining for all these proteins, indicating complement activation in primary lung tumor cells. Importantly, high levels of C1q, C4d, and C5aR1 predict poor disease-free survival (P=0.004; P=0.044; and P=0.02; respectively) and poor overall survival (P=0.031; P=0.022; and P=0.048; respectively) in NSCLC patients. A significant association between PD-1 expression levels in immune cells and disease-free survival was found (P=0.002) but this association was not significant for overall survival. PD-L1 expression levels in both immune cells and tumor cells were not associated with prognosis in NSCLC patients. Interestingly, those patients with high levels of C4d presented a significant decrease of PD-L1 expression in tumor cells (P<0.001) suggesting a link between complement activation and the immune homeostasis of the tumor microenvironment.
8eea62084ca7e541d918e823422bd82e Conclusion
Complement activity in primary NSCLC tumors predicts poor prognosis. C4d, a marker of complement activation, is associated with low levels of PD-L1 expression in tumor cells. Harnessing complement system as therapeutic target may enhance PD-1/PD-L1 immune checkpoint-based immunotherapies.
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P1.03 - Biology (Not CME Accredited Session) (ID 935)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.03-24 - TMPRSS4: A Novel Prognostic Biomarker and Therapeutic Target in NSCLC (ID 11988)
16:45 - 18:00 | Author(s): María José Pajares
- Abstract
Background
Genomic analyses are identifying novel genes involved in the pathogenesis of non-small cell lung cancer (NSCLC). TMPRSS4, a membrane-anchored serine protease, was previously found as highly overexpressed in NSCLC. Since proteases have been functionally related to cancer growth and metastasis, we sought to study the prognostic value and role of TMPRSS4 in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
TMPRSS4 expression was evaluated by immunohistochemistry and H-score calculation in TMAs containing a total number of 455 cases. Kaplan-Meier, log-rank and Cox analyses were used to study the prognostic value. In addition, functional assays using NSCLC cell lines and in vivo models were used to assess the possible role of this protease in NSCLC.
4c3880bb027f159e801041b1021e88e8 Result
High expression of TMPRSS4 was associated with reduced relapse-free survival (RFS, p=0.003) and overall survival (OS, p=0.007) in NSCLC patients. The prognostic value was also found in patients with stages I-II. Multivariant Cox regression analysis identified TMPRSS4 as an independent prognostic factor in NSCLC for both RFS (HR 1.61 [1.16-2.23], p<0.004) and OS (HR 1.52 [1.14-2.03], p<0.005). In functional studies we developed genetic systems to overexpress or reduce TMPRSS4 levels in lung cancer cells lines. Overexpression in LKR13 cells led to increased clonogenicity, migration and multiorganic metastasis in liver, bone and suprarenal gland. Abrogation of TMPRSS4 in H358 and H2170 cell lines caused a very strong reduction in proliferation (>70%, 96h after plating), clonocenicity (>90%, after 15 days in culture) and subcutaneous tumor growth. Reduction in S and G2/M phases of the cell cycle, increased apoptosis, and changes in gene expression of cell replication- and migration-promoting genes (i.e. MCM6, TYMS and CDKN1A(p21)) were also found. Cells lacking TMPRSS4 were highly sensitized to chemotherapy, including cisplatin, paclitaxel and gemcitabine, which significantly enhanced the antiproliferative, antitumor and proapoptotic effect of these drugs.
8eea62084ca7e541d918e823422bd82e Conclusion
Our results show that TMPRSS4 is a biomarker of poor prognosis in NSCLC and plays an important role in tumor growth and metastasis, and suggest that its blockade may enhance sensitivity to chemotherapy.
6f8b794f3246b0c1e1780bb4d4d5dc53
