Reading and Writing the Immune System

In medical school, students are taught to recognize the classic signs of long-term corticosteroid use. One example is moon facies — fat deposits at the cheeks that round out the face.¹ The appearance is unforgettable and, unfortunately, all too common due to the clinical need for broad immunosuppression. The demand for targeted manipulation of the immune system is obvious and affects multiple fields of medicine, including autoimmune disease, cancer immunotherapy and transplant medicine. The next advance in medicine will be immune reprogramming, which induces, modulates or suppresses specific immune responses. In other words, the goal is to read, write and edit immune responses.

1. Reading the Immune System

The first step is to “read” the immune system. The strength of the adaptive immune system lies in its very ability to generate a broad palette of immune cells. A spillover from the explosion of next generation sequencing technologies, T cell receptor sequencing (TCR-seq), captures the palette of immune responses by sequencing the antigen-recognition sites, a unique fingerprint at the receptor that binds to specific targets or antigens.² In cancer immunotherapy, TCR sequencing identifies specific T cell receptor configurations that lead to tumor-killing action.³ Combined with deep-learning methods, TCR repertoire analyses go a step further and reveal the corresponding targets at the T cell receptor recognition site.^4,5 TCR-seq and other sequencing technologies are methods of “reading” the immune responses.

2. Writing the Instructions

The second step is to “write.” A recent development is the use of immunogenic mRNA, a specially modified RNA molecule that is recognized by the immune system. Best known for its use in combating COVID in the form of Pfizer and Moderna vaccines, immunogenic mRNA has a dual role in triggering the innate immune response and in providing genetic instructions for an antigen target for adaptive immunity.⁶ mRNA technology may prove to be a highly flexible platform for inducing immune responses against very specific targets. Highly efficient mRNA vaccines already injected into arms of millions are just one proof of principle of “writing” specific immune responses. Narrowly directed immune responses may be induced against specific tumor types and avoid the broad autoimmune side effects caused by current cancer immunotherapy options.

3. Editing the Response

The last step is to “edit.” Once again, mRNA technology comes into play: Non-immunogenic mRNA can erase immune responses, particularly in the context of autoimmunity. In recent work in a mouse model of multiple sclerosis, non-immunogenic mRNA tricked the immune system into accepting certain antigens as non-threatening.⁷ Non-immunogenic mRNA is the doppelganger of mRNA vaccines, prompting the immune system to ignore certain targets. Existing immune responses can be erased without compromising defenses against pathogens or other targets. Potential applications in rheumatology⁸ and transplant medicine are obvious, as non-immunogenic mRNA can reprogram the immune system to ignore specific self-targets in autoimmune diseases and transplant donor antigens.

Modern medicine has the starting pieces of reading and writing the immune system with powerful sequencing methods and nascent mRNA technologies. Immune reprogramming represents the pinnacle of personalized medicine: tailored immune responses that fit the patient in autoimmunity, cancer immunotherapy and transplant medicine. This will prove to be a great leap forward in immunology and broader health care as we better understand and manipulate our immune system.

References

1. Saag KG, Furst ME. Major side effects of systemic glucocorticoids. UpToDate. Oct 30, 2020.
2. Friedensohn S, Khan TA, Reddy ST. Advanced Methodologies in High-Throughput Sequencing of Immune Repertoires. Trends in Biotechnology, 35, 203-214 (2017). doi: 10.1016/j.tibtech.2016.09.010.
3. Zhang J, Ji Z, et al. Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer. Clin Cancer Res, 26 (6), 1327-1337 (2020). doi: 10.1158/1078-0432.CCR-19-2931
4. Glanville, J., Huang, H., Nau, A. et al. Identifying specificity groups in the T cell receptor repertoire. Nature 547, 94–98 (2017). doi: 10.1038/nature22976
5. Sidhom, JW., Larman, H.B., Pardoll, D.M. et al. DeepTCR is a deep learning framework for revealing sequence concepts within T-cell repertoires. Nat Commun 12, 1605 (2021). doi: 10.1038/s41467-021-21879-w.
6. Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005 Aug;23(2):165-75. doi: 10.1016/j.immuni.2005.06.008.
7. Krienke C, Kolb L, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science, 371 (6525), 145-153 (2021). doi: 10.1126/science.aay3638.
8. Serra, P., Santamaria, P. Antigen-specific therapeutic approaches for autoimmunity. Nat Biotechnol 37, 238–251 (2019). doi: 10.1038/s41587-019-0015-4

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