The Role of Immune Checkpoint Molecules on Macrophages in Cancer, Infection, and Autoimmune Pathologies

Abstract

Immune checkpoint inhibitors have revolutionized immunotherapy against various cancers over the last decade. The use of checkpoint inhibitors results in remarkable re-activation of patients' immune system, but is also associated with significant adverse events. In this review, we emphasize the importance of cell-type specificity in the context of immune checkpoint-based interventions and particularly focus on the relevance of macrophages. Immune checkpoint blockade alters the dynamic macrophage phenotypes and thereby substantially manipulates therapeutical outcome. Considering the macrophage-specific immune checkpoint biology, it seems feasible to ameliorate the situation of patients with severe side effects and even increase the probability of survival for non-responders to checkpoint inhibition. Apart from malignancies, investigating immune checkpoint molecules on macrophages has stimulated their fundamental characterization and use in other diseases as well, such as acute and chronic infections and autoimmune pathologies. Although the macrophage-specific effect of checkpoint molecules has been less studied so far, the current literature shows that a macrophage-centered blockade of immune checkpoints as well as a stimulation of their expression represents promising therapeutic avenues. Ultimately, the therapeutic potential of a macrophage-focused checkpoint therapy might be maximized by diagnostically assessing individual checkpoint expression levels on macrophages, thereby personalizing an effective treatment approach for each patient having cancer, infection, or autoimmune diseases.

Keywords: autoimmune disease; cancer; checkpoint inhibitor; immunodiagnostics; immunotherapy; infection; macrophage; myeloid cell.

Figure 1

Influence of co-regulatory immune checkpoint molecules on macrophage polarization in cancer. In various malignant diseases, the expression of such co-receptors is proven to alter tumor-associated macrophages towards the so-called M2 immune profile with reduced inflammation and thereby mostly “pro-tumor” activity. In contrast, minor expression of immune checkpoints correlates with the M1 macrophage type, characterized by cytotoxic immune cell activity and improved phagocytic ability that results in significant disease clearance. Therefore, inhibition of immune checkpoint expression on macrophages is a highly promising treatment strategy in cancer pathologies. Regarding colorectal cancer, pancreatic cancer and glioblastoma, predominantly PD-1 and CD47 are of great relevance and offer promising targets for checkpoint inhibition. Though, due to the fact that macrophages in different diseases are characterized by expression of different immune checkpoints, the importance of individual therapeutic approaches is highlighted. TAM, tumor-associated macrophages; EMT, epithelial mesenchymal transition.