Patients suffering from non-small cell lung carcinoma (NSCLC) face a poor prognosis, being one of the reasons for the tact that lung cancer is the leading cause of cancer-related deaths worldwide. NSCLC cells gradually develop resistance to the standard-of-care chemotherapy (typically a combination of platinum-based compounds and taxanes). In second line, immunotherapy using immune checkpoint blockers (anti-PD1 or anti-PD-L1) has been approved, illustrating that a further boosting of anti-tumor immunity holds promise to ameliorate the patient's prospects.
A major hurdle tor immunotherapy is the establishment of an immunosuppressive microenvironment in tumors. In this respect, regulatory T cells (Treg) are well known for their immunosuppressive activity and their presence is significantly associated with a poor prognosis in NSCLC patients, strongly suggesting that these cells could be considered as targets for therapy. lmportantly, the body-wide targeting of these cells risks to be toxic (induction of auto-immunity), necessitating the identification of specific markers for tumor-infiltrating Treg. Recently published transcriptomics data on various human cancer types including NSCLC, as well as our own unpublished data in mouse NSCLC models, identified the chemokine receptor CCR8 as a specific marker for a highly suppressive subset of tumor-infiltrating Treg. lnterestingly, the absence of CCR8 results in a reduced tumor growth accompanied by (or caused by) a more immune-permissive tumor microenvironment and higher anti-tumor T-cell activity. Hence, these data suggest that an intratumoral CCR8 signalling pathway contributes to tumor progression and points to CCR8 blockade as a novel therapeutic approach.
Based on these observations, we propose in this study a combination of immunotherapy with the inhibition of CCR8. To achieve this goal, we will screen for novel CCR8 antagonistic Nanobodies, that will be tested for their anti-tumor activity in independent mouse models of NSCLC, either as monotherapy or in combination with immune checkpoint blockers. Hence, the ultimate deliverable of this study should be an optimized protocol for combining immunotherapy with CCR8 inhibition for the treatment of NSCLC in preclinical models, suitable for clinical translation.
Effective start/end date1/04/2031/03/24

    Research areas

  • CCR8, improvement, immunotherapy, non-small cell lung, carcinoma

    Flemish discipline codes

  • Other biotechnology, bio-engineering and biosystem engineering not elsewhere classified

ID: 49766397