Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases

Abstract

To meet the challenges of increasing antimicrobial resistance, the infectious disease community needs innovative therapeutics. Precision medicine and immunotherapies are transforming cancer therapeutics by targeting the regulatory signaling pathways that are involved not only in malignancies but also in the metabolic and immunologic function of the tumor microenvironment. Infectious diseases target many of the same regulatory pathways as they modulate host metabolic functions for their own nutritional requirements and to impede host immunity. These similarities and the advances made in precision medicine and immuno-oncology that are relevant for the current development of host-directed therapies (HDTs) to treat infectious diseases are discussed. To harness this potential, improvements in drug screening methods and development of assays that utilize the research tools including high throughput multiplexes already developed by oncology are essential. A multidisciplinary approach that brings together immunologists, infectious disease specialists, and oncologists will be necessary to fully develop the potential of HDTs.

Keywords: HDT; immuno-oncology; immunometabolism; infectious diseases; precision medicine; tuberculosis.

Figure 1

Pathogenic modulation of immunometabolic activity alters all aspects of immune function and pathogen survival. (A) Within an infected cell, pathogens possess “molecular drivers” (e.g., lipoproteins and glycolipids) that can modulate signaling of key regulatory pathways (e.g., ERK, AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR)) involved in energy metabolism. By affecting the metabolic activity of the infected cell, pathogens alter the immune response contributing to their survival. (B,C) Pathogens can also modulate uninfected immune cells in the microenvironment. (B) By inducing persistent CD4⁺ T cell activation, pathogens cause increased PD-1 expression on CD4 T cells as well as its ligands (e.g., PD-L1) producing an exhausted T cell response. Changes in metabolic activity that occur during both persistent T cell activation and PD-1 signaling significantly contribute to T-cell exhaustion. (C) Suppressor cells [e.g., Tregs, myeloid-derived suppressor cells (MDSCs)] are recruited and activated by infected macrophages through the release molecules that include death-associated molecular patterns and pathogen associated molecular patterns (PAMPs) (e.g., HMGB-1, lipoproteins). Suppressor cells produce an immunosuppressive environment through the production of mediators (e.g., ROS, indoleamine-pyrrole 2,3-dioxygenase, and arginase) that induce oxidative stress, apoptosis, and alter immunometabolic activity.