Research

Lung Cancer is the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the major lung cancer subtype, accounts for 85% of all cases. Most NSCLC patients present with advanced disease at diagnosis, and more than 50% curatively-treated patients experience distant metastasis within 5 years.

Thus, systemic therapy is of paramount importance. Genotype-tailored therapies for patients with oncogene-driven cancers, and immunotherapy based on PD-1 axis blockade, transformed the therapeutic landscape of advanced NSCLC. PD-1 axis inhibitors are now standard of care for a vast majority of NSCLC patients in the first-line setting.

However, only ~15% of the patients truly benefit from PD-1 axis inhibitors, particularly when given as monotherapies. Resistance to PD-1 axis inhibition remains not fully understood, and many of the identified mechanisms (e.g., defects in antigen presentation machinery) are not clinically druggable. Overall, there is a medical need in NSCLC to identify molecular targets and therapeutically amenable mechanisms leading to more efficient treatments that prevent recurrence and metastasis and overcome or prevent resistance to PD-1 axis blockade.

Interleukin (IL)-7, produced by stromal cells, and its receptor (IL-7R), expressed on T-cells, are critical for T-cell differentiation and function, being essential for immune anti-tumor activity. However, IL-7 and IL-7R can also promote cancer progression and resistance to therapy. In the context of leukemia, where IL7R is a bona fide oncogene, high IL-7R levels associate with increased cancer stem cell activity and central nervous system involvement, and IL-7R signaling accelerates tumor expansion, and drives resistance to glucocorticoids.

Some epithelial cancers aberrantly express IL-7R, IL-7 positively impacts breast, bladder and prostate cancer cell lines, and high IL-7/IL-7R levels correlate with poorer survival in breast and prostate cancer. Lung cancer patient samples frequently express high IL7R transcript levels and NSCLC stands out among the solid tumors with reported IL7R gains.

Notably, IL-7R in the tumor tissue of NSCLC patients correlates with lymph node metastasis and poor prognosis. Further, IL-7 activates PI3K/Akt signaling, and fuels proliferation, survival, and VEGF-D production in NSCLC cell lines. These results are tantalizing.

However, conclusive evidence that IL-7R expression in NSCLC cells actively contributes to disease aggressiveness, metastasis and resistance to therapy is still lacking. On the other hand, IL-7 is instrumental for anti-tumor activity, including against lung cancer, and for optimal immunotherapeutic efficacy. In a mouse bladder cancer model, dual PD-1/CTLA-4 inhibition upregulated IL-7R in tumor infiltrating lymphocytes, leading to improved anti-tumor activity. Also, intratumoral secretion of IL-7 induced by oncolytic virotherapy activated and expanded T, NK, and NKT cells in a poorly immunogenic lung carcinoma mouse model.

Is the IL-7-IL-7R axis, critical for immune anti-tumor activity, really subverted towards NSCLC development and resistance to immunotherapy? How? Can we tackle this process therapeutically in order to bypass resistance and improve treatment outcome? Our complementary expertise in IL-7R biology, lung cancer and PD-1 inhibition, and antibody engineering, together with a rational combination of clinical data, patient specimens and unique animal models, will allow us to answer these key questions in a definitive manner. In doing so, we will reveal new insights into lung cancer biology and develop innovative tools to target IL-7R selectively in cancer cells.

Since IL-7R aberrant expression extends beyond lung cancer, the fundamental and clinical impact of our studies can be considerable.