Reinventing the human tuberculosis (TB) granuloma: Learning from the cancer field

Abstract

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world and every 20 seconds a person dies from TB. An important attribute of human TB is induction of a granulomatous inflammation that creates a dynamic range of local microenvironments in infected organs, where the immune responses may be considerably different compared to the systemic circulation. New and improved technologies for in situ quantification and multimodal imaging of mRNA transcripts and protein expression at the single-cell level have enabled significantly improved insights into the local TB granuloma microenvironment. Here, we review the most recent data on regulation of immunity in the TB granuloma with an enhanced focus on selected in situ studies that enable spatial mapping of immune cell phenotypes and functions. We take advantage of the conceptual framework of the cancer-immunity cycle to speculate how local T cell responses may be enhanced in the granuloma microenvironment at the site of Mycobacterium tuberculosis infection. This includes an exploratory definition of “hot”, immune-inflamed, and “cold”, immune-excluded TB granulomas that does not refer to the level of bacterial replication or metabolic activity, but to the relative infiltration of T cells into the infected lesions. Finally, we reflect on the current knowledge and controversy related to reactivation of active TB in cancer patients treated with immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4. An understanding of the underlying mechanisms involved in the induction and maintenance or disruption of immunoregulation in the TB granuloma microenvironment may provide new avenues for host-directed therapies that can support standard antibiotic treatment of persistent TB disease.

Immunosuppression is a conserved driver of tuberculosis susceptibility

“…In line with these findings, prior studies have described increased MDSCs in the blood of Mtb -infected individuals at frequencies similar to those found in human cancer patients 80 as well as increased lung MDSC frequency in non-human primates with active TB disease relative to latently infected animals 81 . Multiple pathways have been proposed for MDSC-driven immunosuppression of the host response against Mtb infection, including PD-1, IDO1, TGFý, and IL-10 82,83 . For example, IDO1 + PD-L1 + myeloid cells reside in human granulomas and PD-L1 expression associates with active TB progression in humans 84 .…”

Breaking barriers: The potential of nanosystems in antituberculosis therapy

“…However, recent research has shown that granulomas, previously considered sites of MTB growth inhibition, may act as sanctuaries for mycobacteria. It has been proposed that granulomas present a more dynamic and intricate structure than originally believed, characterized by interrelated areas with diverse microenvironments [ 59 ]. Additionally, a recent study conducted in zebrafish infected with Mycobacterium marinum showed that monocyte recruitment in the granuloma can favor pathogen proliferation [ 60 ].…”

Dual neutrophil subsets exacerbate or suppress inflammation in tuberculosis via IL-1β or PD-L1

“…The hallmark of TB is the formation of granulomas in the lung; in these organized pluricellular structures, a delicate balance between the containment of Mtb replication and host inflammation takes place. The fate of Mtb, from eradication to active multiplication, may vary depending on the granuloma microenvironment, where multiple immune mechanisms are at play to maintain or disrupt immunoregulation ( 11 ). Among innate cells, neutrophils play dual roles in TB ( 12 ).…”