Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.

http://www.therenegadecell.com/wiki/images/7/7c/Gajewski_T_-_Innate_and_Adaptive_Immune_Cells.pdf

Innate and adaptive immune cells in the tumor microenvironment

Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

/pdf/inflammation-and-tumor-progression-signaling-pathways-and-45r30f9ce8.pdf

Inflammation and tumor progression: signaling pathways and targeted intervention.

Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, Treg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in Treg cells and/or that influence Treg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in Treg cells, but the effects of ICIs on Treg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of Treg cells, whereas cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors might deplete these cells. Thus, although manipulation of Treg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of Treg cells in cancer, which can hopefully be used to develop Treg cell-targeted therapies and facilitate immune precision medicine. Regulatory T (Treg) cells are implicated in cancer immune evasion and escape and thus contribute to tumour development and progression. In this Review, the authors provide an overview of the phenotypes and roles of Treg cells in the context of cancer and outline potential strategies to target this cell type in anticancer immunotherapy.

Regulatory T cells in cancer immunosuppression — implications for anticancer therapy

Leishmania is a genus of protozoan parasites that are transmitted by the bite of phlebotomine sandflies and give rise to a range of diseases (collectively known as leishmaniases) that affect over 150 million people worldwide. Cellular immune mechanisms have a major role in the control of infections with all Leishmania spp. However, as discussed in this Review, recent evidence suggests that each host-pathogen combination evokes different solutions to the problems of parasite establishment, survival and persistence. Understanding the extent of this diversity will be increasingly important in ensuring the development of broadly applicable vaccines, drugs and immunotherapeutic interventions.

Leishmaniasis: complexity at the host–pathogen interface

Dendritic cell (DC)-expressed CD40 is shown to play crucial roles in eliciting effector T cell responses, primarily the proinflammatory CD4 + Th subsets and cytotoxic CD8 + T cells that eliminate various infections and tumors, respectively. In contrast, DCs are also implied in the generation of regulatory T cells (Tregs) that counteract the functions of the proinflammatory Th subsets and exacerbate infections. However, the role of DC-expressed CD40 in the generation of Tregs is unknown. In this study, we generated bone marrow-derived DCs from mice (on a BALB/c background) expressing different levels of CD40 and tested their relative efficiency in generating Tregs. We observed that low levels of CD40 expression were required for efficient Treg generation. DCs expressing low levels of CD40 induced Tregs, whereas DCs expressing high levels of CD40 induced effector T cells, possibly CD8 + CD40 + T cells with a contraregulatory activity; the adoptive transfer of the former DC exacerbated whereas the latter significantly reduced Leishmania donovani infection in BALB/c mice. Similarly, priming of mice with leishmanial Ag-pulsed DCs expressing high levels of CD40 induced host protection against L. donovani challenge infection. In contrast, priming with the low CD40-expressing DC resulted in aggravated infection as compared with the control mice. The results establish that CD40 can play differential roles in Treg differentiation and determine the course of infection. We demonstrate that the knowledge can be efficiently used in adoptive cell transfer therapy against an infectious disease.

/pdf/cd40-expression-levels-modulate-regulatory-t-cells-in-55xitb5007.pdf

CD40 expression levels modulate regulatory T cells in Leishmania donovani infection.

Mammalian target of rapamycin (mTOR) kinases are emerging as master regulators of cellular metabolism [1]. During an infection, pathogens seek nutrition to survive and often exploit host machinery that controls cellular metabolic processes. Moreover, pathogens can subvert host metabolism by targeting mTOR complexes to gain a replicative advantage. Conversely, host cells regulate the mTOR axis to facilitate pathogen clearance. Intriguingly, in addition to their role in the regulation of metabolism, mTOR complexes regulate both the quality and quantity of innate and adaptive immune responses. Here we propose that drugs strategically targeting mTOR, perhaps in opposing ways in distinct cell types, could influence the immunological outcome of host–pathogen interactions and also act as effective antibiotics by limiting pathogen replication.

/pdf/the-battle-over-mtor-an-emerging-theatre-in-host-pathogen-589e93ti7g.pdf

The Battle over mTOR: An Emerging Theatre in Host–Pathogen Immunity

Leishmania donovani, a protozoan parasite, inflicts a fatal disease, visceral leishmaniasis. The suppression of antileishmanial T cell responses that characterizes the disease was proposed to be due to deficiency of a T cell growth factor, IL-2. We demonstrate that during the first week after L. donovani infection, IL-2 induces IL-10 that suppresses the host-protective functions of T cells 14 days after infection. The observed suppression is concurrent with increased CD4+glucocorticoid-induced TNF receptor + T cells and Foxp3 expression in BALB/c mice, implicating IL-2-dependent regulatory T cell control of antileishmanial immune responses. Indeed, IL-2 and IL-10 neutralization at different time points after the infection demonstrates their distinct roles at the priming and effector phases, respectively, and establishes kinetic modulation of ongoing immune responses as a principle of a rational, phase-specific immunotherapy.

/pdf/inhibition-of-il-2-induced-il-10-production-as-a-principle-59nuyi6vhs.pdf

Inhibition of IL-2 induced IL-10 production as a principle of phase-specific immunotherapy.

https://www.cell.com/trends/immunology/pdf/S1471-4906(07)00232-3.pdf

CD40-induced countercurrent conduits for tumor escape or elimination?

CD4(+) regulatory T cells (Treg cells) mediate immunosuppression, whereas CD8(+) T cells confer resistance in many diseases. It is unknown whether CD8(+) T cells confer protection by antagonizing the Treg cells. Using a model of stage-specific immune responses against Leishmania donovani infection in susceptible BALB/c mice, we report that CD3(+)CD8(+)CD40(+) T cells executed CD40-dependent cytotoxicity on CD3(+)CD4(+)CD127(dim)GITR(+)CD25(+) Treg cells during the initial phase of the infection but were later apoptosed by IL-10. CD40 signaled through Ras, PI3K, and protein kinase C, resulting in p38MAPK- or ERK-1/2-independent, but NF-kappaB-dependent, induction of the cytotoxic mediators granzyme and perforin. Adoptive transfer of CD3(+)CD8(+)CD40(+) T cells reduced the L. donovani infection in BALB/c mice. These results identify CD3(+)CD8(+)CD40(+) T cells as the contra-Treg cells and imply a novel immunotherapeutic principle.

CD40 Signaling in CD8+CD40+ T Cells Turns On Contra-T Regulatory Cell Functions

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