Celebrating the 10th Anniversary
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Research
Microsatellite Instability Turns Up the Heat
As immune checkpoint blockade with anti-PD1 and anti-PD-L1 antibodies became a more widely used therapeutic strategy, understanding the expression patterns of immune checkpoint inhibitors and characterizing the composition of tumor immune microenvironment became especially important for attempting to predict which patients might respond. In 2015, Llosa, Pardoll, Housseau, and colleagues comprehensively analyzed the immune microenvironments of a large set of primary colorectal tumors and found dramatically higher levels of tumor-infiltrating CD8+ cytotoxic T lymphocytes and activated IFNγ-secreting T helper type 1 cells – features of what is now referred to as a “hot” immune microenvironment – in approximately 20% of tumors, nearly all of which were characterized by microsatellite instability (MSI) due to defective DNA mismatch repair (MMR). Additionally, expression of inhibitory immune checkpoint receptors such as PD-1, CTLA-4, and LAG3 was significantly higher in MSI compared with non-MSI colorectal tumors, suggesting a mechanism through which tumors can survive in a hostile immune environment and raising the possibility that MSI tumors might be susceptible to immune checkpoint blockade. Based on these findings, phase 2 trials were initiated to test anti-PD-1 antibodies in patients with MSI colon cancer that ultimately showed a dramatic clinical benefit. Significant improvements in progression-free and overall survival were also observed in trials of anti-PD-1 antibodies in other tumor types with MSI or mutations in the MMR pathway. In 2017, the FDA granted its first-ever tissue-agonistic approval to the anti-PD-1 antibody pembrolizumab for treatment of adult and pediatric patients with unresectable or metastatic MSI or MMR-deficient refractory solid tumors, ushering in an era of biomarker-driven drug development. In 2020, pembrolizumab was also approved as a first-line, non-chemotherapy option for patients with unresectable or metastatic MSI or MMR-deficient colorectal cancer.
