Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice.

PPE18 protein belongs to PE/PPE family of Mycobacterium tuberculosis. We reported earlier that PPE18 protein provides survival advantage to M. tuberculosis during infection. In the current study, we found that PPE18 inhibits MHC class II-mediated antigen presentation by macrophages in a dose-dependent manner without affecting the surface level of MHC class II or co-stimulatory molecules. PPE18 does not affect antigen uptake or presentation of preprocessed peptide by macrophages. Antigen degradation was found to be inhibited by PPE18 protein due to perturbation in phagolysosomal acidification. PPE18-mediated inhibition of MHC class II antigen presentation caused poorer activation of CD4 T cells. Mice infected with M. smegmatis expressing PPE18 exhibited reduced maturation and activation of B cells and had decreased Mycobacteria-specific antibody titers. Thus M. tuberculosis probably utilizes PPE18 to inhibit MHC class II antigen presentation causing poorer activation of adaptive immune responses. This study may be useful in understanding host-pathogen interaction and open up directions of designing novel therapeutics targeting PPE18 to tackle this nefarious pathogen.

Dribbling through the host defence: targeting the TLRs by pathogens.

The immune system is well-equipped with sensors that detect invading pathogens and dictate subsequent immune responses for clearing the infections. One such class of sensor is the toll-like receptor (TLR), that can sense diverse molecules of pathogen origin such as proteins, lipids, carbohydrate, DNA, RNA, and trigger suitable immune responses to prevent infections. However, successful pathogens have evolved strategies to bypass the TLR-driven host immune responses to enable their survival inside the host. In this review, we have discussed about the recent advances in TLR biology and strategies adopted by various pathogens (bacteria, virus, and parasites) to subvert the TLR-signalling for evading host-immune attack. Further, we have discussed how TLRs are linked in augmenting infection burden and disease severity in host during co-infection. This information is likely to be helpful to design TLR-based immunotherapeutics to control various infections and pathophysiological disorders.

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis.

Mycobacterium tuberculosis PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) protein binds to TLR2 and triggers a signaling cascade which reduces levels of TNF-α and IL-12, and increases IL-10 in macrophages. Because TNF-α is a major mediator of the pathophysiology of sepsis and blocking inflammation is a possible line of therapy in such circumstances, we tested the efficacy of rPPE18 in reducing symptoms of sepsis in a mouse model of Escherichia coli-induced septic peritonitis. rPPE18 significantly decreased levels of serum TNF-α, IL-1ß, IL-6, and IL-12 and reduced organ damage in mice injected i.p. with high doses of E. coli Peritoneal cells isolated from rPPE18-treated mice had characteristics of M2 macrophages which are protective in excessive inflammation. Additionally, rPPE18 inhibited disseminated intravascular coagulation, which can cause organ damage resulting in death. rPPE18 was able to reduce sepsis-induced mortality when given prophylactically or therapeutically. Additionally, in a mouse model of cecal ligation and puncture-induced sepsis, rPPE18 reduced TNF-α, alanine transaminase, and creatinine, attenuated organ damage, prevented depletion of monocytes and lymphocytes, and improved survival. Our studies show that rPPE18 has potent anti-inflammatory properties and can serve as a novel therapeutic to control sepsis.

TLRs/NLRs: Shaping the landscape of host immunity.

Innate immune system provides the first line of defense against pathogenic organisms. It has a varied and large collection of molecules known as pattern recognition receptors (PRRs) which can tackle the pathogens promptly and effectively. Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are members of the PRR family that recognize pathogen associated molecular patterns (PAMPs) and play pivotal roles to mediate defense against infections from bacteria, fungi, virus and various other pathogens. In this review, we discuss the critical roles of TLRs and NLRs in the regulation of host immune-effector functions such as cytokine production, phagosome-lysosome fusion, inflammasome activation, autophagy, antigen presentation, and B and T cell immune responses that are known to be essential for mounting a protective immune response against the pathogens. This review may be helpful to design TLRs/NLRs based immunotherapeutics to control various infections and pathophysiological disorders.