Immunoactivating the tumor microenvironment enhances immunotherapy as predicted by integrative computational model
Menée à l'aide d'un modèle mathématique prenant en compte le stroma, le système vasculaire et les interactions entres différents types de cellules cancéreuses, de cellules immunitaires et de molécules angiogéniques, cette étude identifie des combinaisons thérapeutiques pour normaliser le micro-environnement tumoral et améliorer les immunothérapie anticancéreuses
The tumor microenvironment, including the tumor immune microenvironment, has been recognized as a complex milieu where cancer cells interact with stromal cells via numerous biochemical and physical signals that are crucial for cancer progression and metastasis (1). Tumor stroma includes blood and lymphatic vasculatures, extracellular matrix (ECM), cancer-associated fibroblasts, and numerous immune cells of the innate and adaptive immune systems, such as T cells, B cells, antigen-presenting cells (e.g., dendritic cells), tumor-associated macrophages, neutrophils, natural killer cells, and myeloid-derived suppressor cells. The important molecules in these cell–cell communications include cytokines (e.g., IL-2, IL-6, IL-10, and IFNγ), chemokines (e.g., CCL2, CCL5, and CXCL12), growth factors (e.g., VEGF, HGF, EGF, TGF-β) and their receptors, and immune checkpoints expressed on cancer and immune cells, such as PD-1, PD-L1, CLTA-4, LAG3, OX40, TIM3, and TIGIT. Tumor cells orchestrate a complex network of immunosuppression to evade elimination by immune cells. Up-regulation of immune checkpoints is an important aspect of this process. In the last decade, immunotherapy in the form of immune checkpoint blockers (ICBs) has emerged as one of the most promising cancer therapies (2). However, the response rate to ICB across different cancer types is only around 13% (3), and the administration of ICB induces drug resistance (4); thus, there is an important unmet need to increase the response rate and also, to determine the signatures of cancer that reliably predict whether patients with these signatures (predictive biomarkers) would respond to a specific immunotherapy or combination therapies. Among different cancer types, tumors are sometimes classified as “cold” and poorly immunogenic or “hot,” inflamed, and immunogenic (5). Also there is significant intertumoral and intratumoral (spatial, cellular, genomic) heterogeneity; in fact, tumor heterogeneity is a hallmark of cancer.The importance of tumor vasculature for tumor progression was demonstrated in studies of Judah Folkman in the 1970s … ↵1Email: apopel{at}jhu.edu.