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Ana Lledo

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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): Ana Lledo

      • Abstract
      • Presentation
      • Slides


      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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