Finding ‘Match for a Mismatch’

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Precision medicine has given hope in managing the disease for the affected individuals after its adoption among the doctors’ community. As the year progressed several new therapies are emerging and proved to be effective against managing cancer despite its stage. One such therapeutic approach for managing recurrent solid tumors/cancer is Immunotherapy. 

We human have our own defense mechanism to counter foreign bodies that enters our body. This defense mechanism is termed as Immune System, it’s a collection of different cells and organs that acts in harmony to neutralize anything that is foreign to the body. 

Cancer cells which are nothing but our normal cell that has been transformed due to aberration in the genome are considered foreign to the body by our immune system, but in this case, cancer cells acquire special ability to bypass our immune check-point mechanism, as result, they aren’t neutralized by our immune system. 

Immunotherapy helps our body’s immune system recognize these abnormal tumor cells and neutralize them with precision without affecting the normal cells, unlike chemotherapy. In the last few years, several guidelines have provided pieces of evidence supporting the use of immunotherapy as an effective treatment tool for recurrent solid malignancies.

Several genomic and proteomic biomarkers have been recommended as a predictive parameter for Immunotherapy decision-making in cancer treatment. As per guidelines TMB, MSI and PD-L1 are three predictive biomarkers for IO treatment decisions.

MSI or Microsatellite Instability is a genomic phenomenon where the conserved repetitive part of our genome is deviated from being normal due to replication error or error in the mismatch repair protein-coding gene of the DNA. The proteins that are responsible for repairing Microsatellite repairing errors are termed MMR (MLH1, MSH2, MSH6, PMS2 are MMR coding genes) or mismatch repair proteins.

The MS region of our genome is very prone to mutation during the replication process. When there are any mutations in the MS region of our genome, MMR proteins come to repair that mutation. The Mismatch Repair proteins are also coded by DNA. If by any means there are any alterations in the coding regions that encode MMR proteins, the error which is accumulated in the MS regions remains unrepaired and passed on from generation to generation. These accumulated errors in the MS regions make our genome unstable hence the name MSI and these phenomena give rise to certain cancers which are also acting as an indicative marker for certain kinds of cancer, like colorectal cancer. 

We all have two copies of our DNA, one from our father and one from our mother. If one copy is mutated for MMR coding genes then the individual is the carrier and also at risk of developing colorectal cancers this event is known as Lynch syndrome. Lynch syndrome is hereditary. So, it is advised to opt for Lynch syndrome genetic screening of anyone whose one of the family members is affected with colorectal cancer. 

Immune responses to cancer are highly variable, with mismatch repair-deficient (dMMR) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (pMMR) tumors. Utilizing this concept clinicians and researchers used MSI as an Immunotherapy predictive Biomarker for cancer treatment. 

Approval of MSI as one of the Immunotherapy markers helped oncologist(s) to widen their personalized treatment for recurrent malignancies. Clinicians don’t have to rely only on PD-L1 expression to take the IO-related treatment decisions, rather information on MSI can also contribute significantly to managing cancer by Immunotherapy. The approval has helped the clinician to provide the best possible treatment benefit to the cancer-affected individual adding value in disease management, it’s like ‘Finding a Match for a Mismatch’.