The 2018 Nobel Prize in Physiology and Medicine was awarded to James P. Allison of the United States and Tasuku Honjo of Japan for their work to identify pathways in the immune system that can be used to attack cancer cells (1). Although immunotherapy for cancer has been a goal for many decades, Dr. Allison and Dr. Honjo succeeded through their manipulation of “checkpoint inhibitor” pathways to target cancer cells.
Immune checkpoint inhibitor drugs have been effective in cancers such as aggressive metastatic melanoma, some lung cancers, kidney, bladder and head and neck cancers. These therapies have succeeded in pushing many aggressive cancers below detectable limits, though these cases are notably not relapse-free or necessarily “cured” (2,3).
One challenge in implementing immunotherapy in a cancer treatment regime is the need to understand the genetic makeup of the tumor. Certain tumors, with specific genetic features, are far more likely to respond to immune checkpoint therapy than others. For this reason, Microsatellite Instability (MSI) analysis has become an increasingly relevant tool in genetic and immuno-oncology research.
What is MSI Analysis?
Deficiencies in DNA mismatch repair (MMR) can be caused by hereditary, germline mutations or hypermethylation. Both mechanisms disrupt expression of functional MMR proteins, allowing transcription errors to accumulate across the genome. Global genomic mutations disrupt normal cellular function, which leads to unchecked growth and cancers but also produces novel proteins. These “foreign” proteins can be immunogenic, recruiting immune effector cells to that tissue. Instability, or mutations, of mononucleotide repeat microsatellite sequences are particularly sensitive to transcription errors and can be the first evidence of an MMR deficiency.
Interest in MSI research exploded with the publication of the paper “PD-1 Blockade in Tumors with Mismatch Repair Deficiency” in the New England Journal of Medicine by Le and colleagues (4). Researchers had long understood that cancer patients with MSI generally had a better prognosis than those without. In colorectal cancers (CRCs), for example, where approximately 15% of tumors show MSI, the tumors are generally less invasive and metastatic, less likely to have a KRAS or p53 mutation, and show a better prognosis under typical treatment conditions (5).
Dr. Le and her associates, though, demonstrated that MSI status correlates with an exceptionally strong response to immunotherapy. In a study of the effects of PD-1 blockade in colorectal cancers, only 1 of 33 samples showed a response. Later, the authors discovered a mismatch repair deficiency in this sample. They found that tumors with this deficiency had high infiltration of immune cells directed at neoantigens, but it was counterbalanced by immune inhibitory ligands such as PD-L1, which binds PD-1 to block T cell activation. When PD-1 is blocked, the immune cells can activate and attack the tumor cells. The authors found that patient serum reflected a clinical benefit after even a single dose of therapy (4).
This paper demonstrated the potential efficacy of immunotherapy in CRCs, but more broadly, it proved that evaluating tumor genomes can help guide immunotherapy.
Since the initial work of Allison and Honjo on the CTLA-4 and PD-1 pathways, many other immune checkpoint signaling pathways have been identified, creating the opportunity for new drug targets. MSI analysis strengthens the arsenal of these drugs by helping to identify those cancers that will respond to these treatment strategy, improving the chances that the most effective therapies are applied to the right tumors for the best outcomes.
- Grady, D. (2018) 2018 Nobel Prize in Medicine awarded to two cancer immunotherapy researchers. https://www.nytimes.com/2018/10/01/health/nobel-prize-medicine.html
- Ritchel, M. (2016) Immunotherapy offers hope to a cancer patient, but no certainty. The New York Times https://www.nytimes.com/2016/08/01/health/immunotherapy-offers-hope-to-a-cancer-patient-but-no-certainty.html
- King, B. (2015) Why cancer is “gone” discourse doesn’t help cancer patients. NPR https://www.npr.org/sections/13.7/2015/12/07/458824962/why-cancer-is-gone-discourse-doesn-t-help-cancer-patients?utm_campaign=storyshare&utm_source=twitter.com&utm_medium=social
- Le, D. et al. (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 37, 2509-20. [PubMed: 26028255]
- Aaltonen, A. et al. (1993) Clues to the pathogenesis of familial colorectal cancer. Science. 260, 812-6. [PubMed: 8484121]
Villaneuva, J. (2018) Dreaming of Universal Tumor Screening. Promega Corporation Web site
Villaneuva, J. (2018) The Evolution of MSI Detection. Promega Corporation Web site
Microsatellite Instability Analysis product page Promega Corporation Web site