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Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy

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The tumor microenvironment (TME) is an integral part of cancer. Recognition of the essential nature of the TME in cancer evolution has led to a shift from a tumor cell-centered view of cancer development to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. Accordingly, novel targets within the TME have been uncovered that can help direct and improve the actions of various cancer therapies, notably immunotherapies that work by potentiating host antitumor immune responses. Here, we review the composition of the TME, how this attenuates immunosurveillance, and discuss existing and potential strategies aimed at targeting cellular and molecular TME components.


Although much focus in cancer biology has been directed on cancer cell genetic and epigenetic alterations that drive malignancy, a wealth of new information has emerged revealing how the functionality of the tumor microenvironment (TME) determines its integral and indispensible role in tumor anatomy and physiology. It is now increasingly accepted that, rather than working alone, cancer cells interact closely with the extracellular matrix (ECM) and stromal cells, which together form the major construct of the TME [1]. Within the TME infrastructure, a variety of immune and non-immune cell types are found and, with the many factors that they secrete, these drive a chronic inflammatory, immunosuppressive, and pro-angiogenic intratumoral environment. Cancer cells are able to adapt and grow in such environments with significantly less likelihood of detection and eradication by host immunosurveillance. As our knowledge of the TME increases, so does the number of biological molecules and mechanistic pathways potentially targetable for cancer treatment. Here, we review the input of the TME in existing development along with current and future TME-targeting treatment strategies.

The composition of the TME and its interaction with the host immune system

A variety of cell types are found in the TME, which accumulate at different stages of tumor development. Some of the principal cell types to arrive in tumors during their early development are infiltrating inflammatory cells, bone marrow-derived hematopoietic and endothelial progenitor cells, and carcinoma-associated fibroblasts [2]. Early infiltration of tumors by immune cells such as macrophages, lymphocytes, natural killer (NK) cells, and dendritic cells (DCs) is crucial for tumor control [3]. The anticancer immune response generated by these cells is, however, inhibited by the action of immunosuppressive cells, such as myeloid-derived suppressor cell (MDSC) regulatory T cells (Tregs), and type 2-polarized macrophages (M2), which are intrinsically associated with the developing TME (Figure 1) [3, 4]. Cancer cells are able to communicate with other cells and components of the TME through two principal pathways: the first being contact-dependent mechanisms between the particular cancer cell and another cell or with the ECM and the second being contact-independent mechanisms via soluble molecules such as cytokines, lipid mediators, and growth factors. The stromal cells that form a constitutive part of the TME are originally recruited either from the surrounding tissues or from the bone marrow, these making up the cellular components such as endothelial cells, mesenchymal cells, fibroblasts, and myeloid and lymphoid inflammatory cells [1, 5]. Within the TME, stromal cells can become ‘educated’ to become a variety of other cell types that facilitate and sustain cancer cells. This is able to occur due to the phenomenal nature of the TME, which is one of chronic inflammation [6].

Figure 1. Good guys versus bad guys in the tumor microenvironment: a balance.

Targeting the tumor microenvironment: removing obstruction to anticancer  immune responses and immunotherapy - Annals of Oncology

The balance between a large number of different immune cells, immune factors, and signaling molecules determines the outcome of the antitumor immune response. CTL, cytotoxic T lymphocyte; Th, T helper; pTh17, pathogenic T helper 17; NK, natural killer; DC, dendritic cell; IFN, interferon; IL, interleukin; GM-CSF, granulocyte macrophage colony-stimulating factor; TGF, transforming growth factor; IDO, indole 2,3-dioxygenase; PGE, prostaglandin E; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage.

Effects of Th1/Th2 on tumor progression

Naive T cells become Th1 cells or Th2 cells, following the stimulation by different factors. In Th1 immunity, cells produce pro-inflammatory cytokines, such as interleukin-2 (IL2), interferon-gamma (IFN-γ), and tumor necrosis factor-beta (TNF-β). In Th2 immunity, cells produce antiinflammatory cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13. In normal circumstances, Th1 immunity and Th2 immunity approach a balance. But, the presence of tumor cells disrupts this balance. This occuring increased Th2 immunity and decreased Th1 immunity, because of down-regulation of adaptive immunity. This eventually leads to tumor progression. However, if Th1 immunity becomes predominant, this stimulation of immunity can lead to tumor regression.

Effects of Th1/Th2 on tumor progression. Naive T cells become Th1 cells...  | Download Scientific Diagram

laika, Daniel, laika and 1 people reacted
Joined: 8 months ago
Posts: 124
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Factors that May Increase Cytotoxic T Lymphocyte Cells (CTLs)  

Factors that May Increase Type 1 T Helper (Th1)

  1. Sun/UVB light [1]
  2. ProbioticsS Boulardii? [5], L. Sporogenes, L Acidophilus [6], L casei [7], Lactobacillus rhamnosus GG [8], Lactobacillus paracasei [9], Lactobacillus salivarius [9], B Longum [10], L Brevis [11], L fermentum [12].
  3. NAC/Glutathione [14]
  4. Licorice -18/β-glycyrrhetinic acid+LicoA [15, 16]
  5. Gynostemma [19]
  6. Ginger or juice the root [20, 21]
  7. Reishi [22]
  8. Tinospora [23]
  9. Quercetin [24]
  10. Astragalus [25]

Factors that May Increase T Helper 17 (Th17)

  • Gluten [150]
  • Iodine excess [151]
  • Arginine [141]
  • High salt diet [154]
  • Long-chain fatty acids [155]

Factors that May Increase Natural Killer Cells (NK)

Factors that May Increase Interferon Gamma (INF-γ)

johan and johan reacted
Joined: 4 years ago
Posts: 1190

A few more options to your list of Factors that May Increase Natural Killer Cells (NK):

Reduced lactate levels improve NK cell activity
Enzymatically modified rice bran
Panax ginseng
Cardamom & black pepper (work synergistically)
Turkey Tail
Active Hexose Correlated Compound
Modified citrus pectin
MYO X (inhibition of activin-A by follistatin)


laika, medline, laika and 1 people reacted