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Controlling TIME: Tumor Immune Microenvironment

Tumor Microenvironment

While the “Tumor immune microenvironment”, or TIME, is not a new concept in cancer research, advances in technology and scientific methods have opened new ways for researchers to look more deeply into the biology of tumor interactions with the immune system.  


Malignant cells in the body tend to spread and grow to affect other areas. The microenvironment of tumor cells has significant effects on surrounding tissue, and tumor cells can rapidly spread to annex adjacent cells.


The host's immune system raises a specific response to try to prevent the spread of tumor cells and provide the host with protection, generating a range of anti-tumor immune cells. Scientists have been seeking out ways to identify and better understand the methods used by the body's immune system, and utilize that in treatment. Immunotherapy works to treat diseases including cancer by either activating or suppressing the patient’s immune response. 


There have been various studies and clinical trials to identify the results and benefits of immunotherapy, with mixed results. Advances in tools, methods and drugs have opened new horizons for immunotherapies to prohibit the spread of the microenvironment of tumor cells within the body.  (1)


TIME in relation to tumor progression


It was once deemed impossible for a host's immune system to prohibit the spread of the microenvironment of tumor cells, but a whole new debate has recently opened up in the field of tumor progression. 


Immunotherapy requires new preclinical methods, models and research questions. Previous methodologies, looking for the growth of infected cells under 2D modelling, has shed light on ‘intrinsic growth’ and the advancement of cells in the body. However, this strategy is not enough to help researchers understand tumor growth in the tumor-immune microenvironment.


Modelling of the TIME will require mapping of all the associated variables, which had been previously hidden from the insight of the researcher. The most important variables and considerations include physical and chemical barriers that can prove useful in understanding tumor progression. Immunotherapy focuses on the behavior of the infected cells and the extracellular matrix (ECM) composition (2). 3D models of cells, their ECM, and immunotherapy together may open new drug development routes that could prove more effective in preventing progressive cancer cells. 


To begin with, a tumor cell is isolated and hard to detect. There are no significantly affected areas in the host body that offer information about early progression and allow for a diagnosis. With time, the single cell proliferates and the number of heterogeneous cells increases. These heterogeneous cells have the power to change and remodel the entire environment in the adjacent cells. The new tumor cells remain hidden from the host's immune system initially and can thrive, proliferating into significant numbers in the host body without any symptoms. The initial handful of cancer cells thus increase in number and develop the ability and power to create a bigger tumor that can visibly affect the area. The extracellular matrix will contribute to the infiltration of tumor cells into the healthy and unaffected neighbouring cells. Now the tumor gains consistency, becoming visibly hard, and can be identified with the help of tests and diagnosis. 


The tumor creates its own microenvironment, which is filled with cancer associated fibroblasts (CAFs). This is followed by the epithelial to mesenchymal transition (EMT) and the generation of both pre- and pro-inflammatory cytokines such as IL-1β, IL-6, TNFα. This will further lead to angiogenesis and immune evasion and release of anti-inflammatory cytokines IL-10 and Il-35 along with TGFβ and M-CSF. 


Advantages of targeting the TIME


Immunotherapy has evolved in the past few decades to identify the tumor cell microenvironment that tumour cells work so hard to keep hidden. Immune checkpoint inhibitor drugs, which block proteins called checkpoints made by immune and cancer cells to limit the effectiveness of the immune system, are a relatively recent development in cancer treatments. But in 3D modelling, this type of immunotherapy shows more promising results for diagnosing tumor cells in their early stages than more established treatment


Understanding of the TIME is paving the way for immune checkpoint therapies that can block cancer-induced checkpoint inhibition, restoring proper immune function in the tumour microenvironment. This allows the body to detect and attack the cancer cells. The first drug targeting an immune checkpoint in cancer, CTLA4 blocker ipilimumab, was approved only a decade ago in 2011. Today immunotherapies focused on the TIME include multiple checkpoint inhibitors targeting PD-1 and PD-L1 as well as CTLA4, with the CISH molecule also a target of interest for its potential to radically enhance cancer immunotherapies. 


Further research on immunotherapy is also helping researchers mitigate some of the side effects associated with checkpoint therapies, which can cause diverse immune-related inflammatory events throughout the body. Colitis, hypothyroidism and neuromuscular disease myasthenia gravis have all been associated with immune checkpoint inhibition, but studies show that some of these impacts can be reduced by combining treatment with other drugs, providing hope for more effective early-stage cancer treatment with fewer side effects in future (4).


How controlling the TIME can be helpful to researchers in drug development


The latest research and advances in controlling the TIME are helping us to understand how tumors can stay hidden from immune cells. Once scientists learn ways to identify the methods by which tumor cells isolate and protect themselves from immune cells, they can find ways to fight cancer at all the different stages of tumor development. 


The TIME is helping researchers discover improvised checkpoints that are assisting early-stage tumor cells. With more focused research on controlling TIME, researchers will understand how all the different tumor cells create their microenvironment and infect the adjacent areas. Once the process, routine, and mechanism for creating the microenvironment in the host is fully understood, researchers will know how to infiltrate that environment to destroy the tumor in the early stages (5).


Since a tumor starts from a single cell, and this individual entity has the capability to stay hidden from  immune cells, doctors are helpless to find these early invaders that can go on to create such damage in surrounding tissue. Increased understanding of the TIME will offer more ways of managing cancer and help researchers create new drugs, both to identify tumor cells early on and to ward off these cells from the host body without any potential side effects. 



1. Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., . . . Hedrick, C. C. (2018). Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature medicine, 24(5), 541-550. 

2. Taube, J. M., Galon, J., Sholl, L. M., Rodig, S. J., Cottrell, T. R., Giraldo, N. A., . . . Rimm, D. L. (2018). Implications of the tumor immune microenvironment for staging and therapeutics. Modern Pathology, 31(2), 214-234. Xiong, Y., Wang, Y., & Tiruthani, K. (2019). Tumor immune microenvironment and nano-immunotherapeutics in colorectal cancer. Nanomedicine: Nanotechnology, Biology and Medicine, 21, 102034. 

3. Saeed, M., Gao, J., Shi, Y., Lammers, T., & Yu, H. (2019). Engineering nanoparticles to reprogram the tumor immune microenvironment for improved cancer immunotherapy. Theranostics, 9(26), 7981.

4. Risbjerg RS, Hansen MV, Sørensen AS, Kragstrup TW. The effects of B cell depletion on immune related adverse events associated with immune checkpoint inhibition. Exp Hematol Oncol. 2020;9:9. Published 2020 May 25. doi:10.1186/s40164-020-00167-1

5. Neal, J. T., Li, X., Zhu, J., Giangarra, V., Grzeskowiak, C. L., Ju, J., . . . Smith, A. R. (2018). Organoid modeling of the tumor immune microenvironment. Cell, 175(7), 1972-1988. e1916.


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