/pdf/a-toll-like-receptor-recognizes-bacterial-dna-2lif1icvoq.pdf

A Toll-like receptor recognizes bacterial DNA

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.

Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-CELL suppressive activity

The purpose of immunology is simple. Cure or prevent disease. M1/M2 is useful because it is simple. M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage while M2 activity promotes cell proliferation and tissue repair. Remarkably, the molecules primarily responsible for these "Fight" (NO) or "Fix" (Ornithine) activities both arise from arginine, and via enzymatic pathways (iNOS and arginase) that down regulate each other. The names M1 and M2 were chosen because M1 and M2 macrophages promote Th1 and Th2 responses, respectively. Products of Th1 and Th2 responses (e.g., IFN-γ, IL-4) also down regulate M2 and M1activity, respectively. Thus, M1/M2 demonstrated the importance of Innate Immunity and how it is linked to Adaptive Immunity in a beautifully counterbalanced system. "Civilization" and increased longevity present new disease challenges such as cancer and atherosclerosis that do not display classical "foreign" antigens. And, these diseases are often associated with (or caused by) M1- or M2- type responses that were formerly useful for fighting infections, but now are inappropriate in our increasingly "germ-free" societies. In turn, there is considerable potential for modulating M1 or M2 Innate responses in modern diseases to achieve better health. Finally, since M1 and Th1 (or M2 and Th2) often work in concert to produce characteristic immune responses and disease pathologies, it is recommended that Immune Type 1 or 2 (IT1, IT2) would be a simpler and unifying terminology going forward.

M1 and M2 Macrophages: Oracles of Health and Disease.

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs trigger cells that express Toll-like receptor 9 (including human plasmacytoid dendritic cells and B cells) to mount an innate immune response characterized by the production of Th1 and proinflammatory cytokines. When used as vaccine adjuvants, CpG ODNs improve the function of professional antigen-presenting cells and boost the generation of humoral and cellular vaccine-specific immune responses. These effects are optimized by maintaining ODNs and vaccine in close proximity. The adjuvant properties of CpG ODNs are observed when administered either systemically or mucosally, and persist in immunocompromised hosts. Preclinical studies indicate that CpG ODNs improve the activity of vaccines targeting infectious diseases and cancer. Clinical trials demonstrate that CpG ODNs have a good safety profile and increase the immunogenicity of coadministered vaccines.

/pdf/cpg-dna-as-a-vaccine-adjuvant-154sl6aa4k.pdf

CpG DNA as a vaccine adjuvant

A comprehensive understanding of host-pathogen interactions requires a knowledge of the associated gene expression changes in both the pathogen and the host. Traditional, probe-dependent approaches using microarrays or reverse transcription PCR typically require the pathogen and host cells to be physically separated before gene expression analysis. However, the development of the probe-independent RNA sequencing (RNA-seq) approach has begun to revolutionize transcriptomics. Here, we assess the feasibility of taking transcriptomics one step further by performing 'dual RNA-seq', in which gene expression changes in both the pathogen and the host are analysed simultaneously.

/pdf/dual-rna-seq-of-pathogen-and-host-1dk955su2j.pdf

Dual RNA-seq of pathogen and host

https://www.mdpi.com/2076-393X/3/2/390/pdf

CpG Oligonucleotides as Cancer Vaccine Adjuvants.

FDA guidance on prophylactic DNA vaccines: Analysis and recommendations

The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors. Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500–800 mm3) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated. The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity. The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.

https://jitc.bmj.com/content/jitc/2/1/12.full.pdf

Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors

Tumors persist by occupying immunosuppressive microenvironments that inhibit the activity of tumoricidal T and NK cells. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of this immunosuppressive milieu. We find that the suppressive activity of mMDSC isolated from cancer patients can be reversed by treatment with TLR7/8 agonists, which induce human mMDSC to differentiate into tumoricidal M1-like macrophages. In contrast, agonists targeting TLR1/2 cause mMDSC to mature into immunosuppressive M2-like macrophages. These two populations of macrophage are phenotypically and functionally discrete and differ in gene expression profile. The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy.

/pdf/effect-of-tlr-agonists-on-the-differentiation-and-function-bejlk20az9.pdf

Effect of TLR Agonists on the Differentiation and Function of Human Monocytic Myeloid-Derived Suppressor Cells

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs mimic the immunostimulatory activity of bacterial DNA. CpG ODN directly stimulate human B cells and plasmacytoid dendritic cells, promote the production of Th1 and proinflammatory cytokines, and trigger the maturation/activation of professional APC. CpG ODN are finding use in the treatment of cancer, allergy, and infection. In contrast, ODN containing multiple TTAGGG motifs mimic the immunosuppressive activity of self-DNA, down-regulating the production of proinflammatory and Th1 cytokines. Preclinical studies suggest that “suppressive” ODN may slow or prevent diseases characterized by pathologic immune stimulation, including autoimmunity and septic shock. Extensive studies in animal models suggest that the therapeutic value of CpG and TTAGGG ODN may be optimized by early administration.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1107775

Debra Tross

Papers

CpG Oligonucleotides as Cancer Vaccine Adjuvants.

FDA guidance on prophylactic DNA vaccines: Analysis and recommendations

Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors

Effect of TLR Agonists on the Differentiation and Function of Human Monocytic Myeloid-Derived Suppressor Cells

Synthetic oligonucleotides as modulators of inflammation