Tumor Microenvironment, Inflammation, and Resistance to Immunotherapies

The tumor microenvironment (TME) is the complex ecosystem surrounding a tumor which includes the extracellular matrix, blood vessels, and stromal cells. It also encompasses different types of immune cells, such as neutrophils, dendritic cells, natural killer (NK) cells, T-cells and B-cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Inflammatory cells are indeed an essential component of the TME since cancer cells can hijack inflammatory mechanisms in favor of their own growth and survival. Modulating the immune system to recognize and eliminate cancer cells is the goal of immunotherapies, but cancer cells within the TME respond differently to various types of immunotherapies, according to their underlying molecular profile. This tremendously affects the response of cancer patients to immune checkpoint inhibition (ICI) therapies, targeting mainly the PD-1/PD-L1 axis and CTLA-4, but also adoptive cell transfer (ACT) or genetically-modified T-cell receptor (TCR) and Chimeric Antigen Receptor (CAR-T) based therapies, all of which have been intensely examined and used as new immunotherapies in cancer treatment. Although there are examples of immunotherapies that have yielded impressive results in different cancer patients, the problem is that the majority of patients fail to develop durable responses. The causes of immunotherapy resistance remain largely unknown and many different molecular factors have been implicated. For instance, inhibitory immunoregulatory pathways can directly hamper cancer cell elimination by cytotoxic T cells. Further, recent evidence suggests the involvement of the epithelial-mesenchymal transition (EMT), inflammation, and hypoxia, in addition to immune dysregulation within the TME and the tumor’s mutational landscape. Therefore, a better understanding of the key immunosuppressive and resistance mechanisms associated with a complex TME can provide new avenues to limit immune escape, develop new therapeutic strategies, and tailor efficient treatments. The scope of this special issue is to evaluate our current knowledge on how the interplay of cancer cells with immune cells within the TME impacts resistance of cancer cells to ICI, ACT or TCR/CAR-T based immunotherapeutic approaches, aiming to find ways to overcome this hurdle and improve patient response to immune-based interventions. We thus welcome both original research and review articles dealing with the tumor microenvironment, inflammation, and resistance of cancer patients to immunotherapies.