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Final Report Summary - TIMCC (Tumor Infiltrating Myeloid Cell Compartment)

For a long time cancer was considered to be uncontrolled cell growth mainly caused by DNA damage as a result of, for example, strong exposure to the sun or aging. However, recently it has been recognised that the interaction between the tumour cell and its micro-environment is crucial for its development from a benign to a malignant and eventually metastasizing tumour. Within the tumour micro-environment (TME) cells of the immune system are prominently present. That is not surprising because it is generally accepted that the immune system not only protects against intruders such as bacteria, but also recognises and eliminates abnormally growing cells. Therefore it was a big shock when it became clear that the immune cells in the TME do not participate in an anti-tumour response but foster tumour growth and promote metastasis. According to these observations cancer should not be considered as a problem of exclusively abnormally growing cells, but as a complex disease in which the interaction between the immune system and the proliferating tumour cells determines the outcome of the disease. Thus the immune system itself is part of the problem and is a potential target for therapy. The majority of the tumour infiltrating immune cells consists of a variety of myeloid cells. Myeloid cells are the vacuum cleaners in the body which are quickly alarmed to remove bacteria that infect the body or, when tissue is damaged, to clean the wound. Importantly these cells are strong regulators of other slower reacting but more specific and effective immune cells. The tumour infiltrating myeloid cell compartment (timcc) prevents these more specific immune cells to enter the TME and to display their tumour killing activity. It is not clear whether the tumour hijacks the myeloid cells to protect itself against attacks of other immune cells and to foster its growth or if the immune system is simply misguided and considers the tumour as a wound that needs to be healed (but cannot heal). It is not well understood how the timcc promotes tumour growth and how it prevents an effective anti-tumour response by the immune system and hampers effective therapy.

Research activities and results
In the TIMCC network we brought together eight expert teams from different disciplines within immunology, genetics and oncology to provide substantial and methodological training in the analysis of the role of the timcc in cancer and cancer therapy. By applying advanced technology, the network was able to isolate and characterise individual myeloid cells from a variety of human and mouse tumours untreated and treated with different types of therapy. The timcc appeared a very heterogeneous cell population with mainly a ‘pro-tumour’ and immune suppressive signature. Corresponding experimental preclinical models of human tumours, more easily accessible for experimental research, showed comparable patterns. Depletion of distinct subpopulations of myeloid cells from tumour bearing mice improved the efficacy of chemotherapy, suggesting that these cells hamper the therapy and therefore are potential targets in combination therapy. However, in another type of therapy in another tumour model particular myeloid cells were indispensable for the therapeutic efficacy, illustrating the complexity of the system. By using mice that lack a specific subtype of myeloid cells, the mast cell, it was demonstrated that these cells, although abundantly present in the TME, have no role in tumour development in contrast to other myeloid cells.
The protection by the immune system is based on its capability to discriminate between ‘self’ and ‘non-self’. That is easy to achieve during a bacterial infection but becomes tricky in case of cancer. Tumour cells, although somewhat abnormal, are mainly ‘self’. To avoid self-destruction the immune response to tumours is in general weak. However, it has been recently shown that so called immunotherapy, boosting this weak response, can result in effective eradication of the tumour. Immunotherapy is booming. The results of the TIMCC network research program indicate that the timcc has a strong impact on the outcome of immunotherapy. It is generally believed that an effective immunotherapy requires the selective depletion and/or ‘reprogramming’ of the timcc to optimise the tumor antagonizing activity of the immune system.

The TIMCC training and research program gathered knowledge and taught the skills necessary to develop new therapeutic strategies that on the one hand promote the tumor antagonistic properties of the timcc and on the other hand suppress its tumor-promoting properties. These strategies will become an intrinsic part of future successful immune-oncology combination therapies.
The TIMCC training program delivered a series of young researchers with multidisciplinary biomedical knowledge, skill-sets and key insights into the complexity of translational medicine fully equipped to develop these new combination therapies.

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