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Researchers have manipulated the immune system to respond more aggressively to cancer according to a new study [1].

Manipulating macrophages

We have discussed modulating the immune system multiple times recently, especially in regards to macrophages and manipulating their behavior. Macrophages are part of the innate immune system and carry out a wide variety of tasks, such as clearing away cell debris, engulfing pathogens, facilitating tissue growth, and disposing of senescent cells once other immune cells have destroyed them.

Macrophages have a certain behavioral pattern that determines how they act and respond to stimuli; this is known as polarization. The polarization of macrophages can be broadly divided into two types, M1 and M2, although this is a simplification of what is actually a subtle range of states.

In broad terms, the M1-type macrophages are proinflammatory and aggressive, while the M2-type macrophages favor anti-inflammatory activity and focus on tissue repair following injury. In order for the immune system to function properly, a suitable balance between these two polarizations is required. When that balance is disrupted and the ratio of M1 and M2 macrophages is wrong, this can lead to problems.

Having too many M1 types and too few M2 leads to excessive inflammation and contributes to many age-related inflammatory conditions. Therefore, recent focus has moved to manipulating the ratios of M1 and M2 macrophages to combat various diseases.

In the case of age-related inflammatory conditions, the ratio needs to shift towards a more healing profile, so more M2 macrophages need to be encouraged to facilitate tissue healing and repair. This leads to a healing environment that favors reduced inflammation, which, for those conditions, is good.

However, in the case of cancer, the opposite is desirable; the more M1-type macrophages in the cancer environment there are in the short term, the more aggressively it can be fought. These researchers have focused on increasing the number of M1 macrophages, and they have presented some promising results.

Effectively activating macrophages that can ‘eat’ cancer cells is challenging. In particular, cancer cells secrete macrophage colony stimulating factor (MCSF), which polarizes tumour-associated macrophages from an antitumour M1 phenotype to a pro-tumorigenic M2 phenotype. Also, cancer cells can express CD47, a ‘don’t eat me’ signal that ligates with the signal regulatory protein alpha (SIRPα) receptor on macrophages to prevent phagocytosis. Here, we show that a supramolecular assembly consisting of amphiphiles inhibiting the colony stimulating factor 1 receptor (CSF-1R) and displaying SIRPα-blocking antibodies with a drug-to-antibody ratio of 17,000 can disable both mechanisms. The supramolecule homes onto SIRPα on macrophages, blocking the CD47–SIRPα signalling axis while sustainedly inhibiting CSF-1R. The supramolecule enhances M2-to-M1 repolarization within the tumour microenvironment, and significantly improves antitumour and antimetastatic efficacies in two aggressive animal models of melanoma and breast cancer, with respect to clinically available small-molecule and biologic inhibitors of CSF-1R signalling. Simultaneously blocking the CD47–SIRPα and MCSF–CSF-1R signalling axes may constitute a promising immunotherapy.

Conclusion

As our understanding of the immune system grows and our ability to manipulate it towards more favorable activity increases, we take further steps towards combating diseases by using our own cells.

As we age, the immune system becomes increasingly dysfunctional due to inflammation from various sources, so controlling that inflammation and manipulating our immune system to work better are promising avenues of research in the fight against cancer and aging.

Literature

[1] Ashish Kulkarni, Vineethkrishna Chandrasekar, Siva Kumar Natarajan, Anujan Ramesh, Prithvi Pandey, Jayashree Nirgud, Harshangda Bhatnagar, Driti Ashok, Amrendra Kumar Ajay & Shiladitya Sengupta. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer (2018) Nature Biomedical Engineering.

About the author

Steve Hill

As a scientific writer and a devoted advocate of healthy longevity and the technologies to promote them, Steve has provided the community with hundreds of educational articles, interviews, and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).
  1. July 4, 2018

    Cancer cells can also over express MHC class 1 to avoid phagositosis by macrophages:

    https://www.nature.com/articles/s41590-017-0004-z

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