Toll-Like Receptors (TLRs) in the Tumor Microenvironment (TME): A Dragon-Like Weapon in a Non-fantasy Game of Thrones.

Toll-like receptors (TLRs) in the tumor microenvironment (TME) are expressed not only in innate and adaptive immune cells but also in stromal cells such as fibroblasts, endothelial cells (EC), and tumor cells. The role of TLR signaling in the TME is complex and controversial due to their wide expression within the TME. Moreover, TLR signaling may culminate in different outcomes depending on the type of tumor, the implicated TLR, the type of TLR ligands, and, most importantly, the main type of cell(s) that are targeted by TLR ligands. Understanding to what extent these complex TLR signals impact on tumor progression merits further investigation, as it can help improve existing anti-cancer treatments or unravel new ones. In most cases, TLR signaling in tumor cells and in immune cells is associated with pro-tumoral and anti-tumoral effects, respectively. A better understanding of the relationship between TLRs and the TME, especially in humans, is required to design better anti-cancer therapies, considering that most current TLR-involved treatments were disappointing in clinical trials.In this chapter, we will discuss the impact of TLR signaling on the hallmarks of cancer, by highlighting their effects in tumor, immune, and stromal cells within the TME. Furthermore, we will discuss how the understanding of the role of TLRs can pave the way to develop new anti-cancer treatments and even predict clinical outcome and chemotherapy efficacy.

Acute Influenza Infection Promotes Lung Tumor Growth by Reprogramming the Tumor Microenvironment.

One billion people worldwide get flu every year, including patients with non-small cell lung cancer (NSCLC). However, the impact of acute influenza A virus (IAV) infection on the composition of the tumor microenvironment (TME) and the clinical outcome of patients with NSCLC is largely unknown. We set out to understand how IAV load impacts cancer growth and modifies cellular and molecular players in the TME. Herein, we report that IAV can infect both tumor and immune cells, resulting in a long-term protumoral effect in tumor-bearing mice. Mechanistically, IAV impaired tumor-specific T-cell responses, led to the exhaustion of memory CD8+ T cells and induced PD-L1 expression on tumor cells. IAV infection modulated the transcriptomic profile of the TME, fine-tuning it toward immunosuppression, carcinogenesis, and lipid and drug metabolism. Consistent with these data, the transcriptional module induced by IAV infection in tumor cells in tumor-bearing mice was also found in human patients with lung adenocarcinoma and correlated with poor overall survival. In conclusion, we found that IAV infection worsened lung tumor progression by reprogramming the TME toward a more aggressive state.

To Vaccinate or not: Influenza Virus and Lung Cancer Progression.

Influenza virus infection leads to severe and complicated disease, particularly in patients with lung cancer. It alters the tumor microenvironment (TME), which may potentiate lung cancer progression and disrupt responses to antitumoral treatments. Consequently, influenza vaccination and antiviral treatments should be recommended to all patients with lung cancer.