Maria Libera Ascierto
Maria Libera Ascierto, Ph.D, Johns Hopkins University, USA 733 South Ann St, Baltimore, MD
Title: The molecular profiling of immunotherapeutic resistance
Biography
Biography: Maria Libera Ascierto
Abstract
: After Coley’s observation in 1891 of tumor regression in a patient who developed a postoperative infection, the field of cancer immunology is finally reborn. Cancer patients with active adaptive and innate arms of immunity display clinical benefit (1, 2, 3). Accordingly, avoiding immune destruction is now considered a hallmark of cancer, and the immunotherapy arena has exploded with the recent advances demonstrating an improvement in survival and a durability of response in patients with different cancer types, including melanoma (4). In this regard, monoclonal antibodies blocking programmed death 1 (PD-1):PD-1 ligand (PD-L1, B7-H1) pathway showed an unprecedented spectrum of activity versus different cancer types providing a “common denominator” for cancer therapy. Despite these very encouraging results, the majority of patients do not respond to these regimens as monotherapy leading to an urgency to identify biomarkers that accurately predict which patients will benefit from this form of therapy. At the same time, there is a critical need to identify potentially actionable mechanisms of therapeutic resistance to anti-PD-1 or anti- PD-L1 therapies in order to set successful combinatorial approaches. The expression of PD-L1 on the tumor cell surface has been previously identified as one factor associated with the clinical activity of anti–PD-1. Notably, a significant number of patients with PD-L1+ cells still do not respond to PD-1 pathway blockade, suggesting that additional factors can induce therapy resistance thus influencing treatment outcomes (5). In renal cell carcinoma, we showed with a deep molecular analysis that the intra-tumor balance between metabolic and immunologic gene expression might determine the effective response to anti-PD-1 blockade (6). In melanoma, we discovered transcriptional signatures mostly associated with epithelial to mesenchymal transition (EMT) and accumulation of neutrophils to be associated with PD-1 blockade therapy resistance (7). These studies suggested that many pathways might determine the clinical response to anti-PD-1 therapy in cancer patients and that determinants of clinical response might change based on the considered tumor type.