Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Their impactful studies. In their words.
Our work has provided a framework for high-impact studies over the years, integrating immunology, oncology, and genomics to understand the diversity of the tumor microenvironment in colon cancer, which can be exploited for designing new combinatorial immunotherapies.
The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
Q: What unanswered questions in the field was this study addressing?
A: (Franck Housseau) This work allowed us to understand how the density of neoantigens could associate with the immunogenicity of microsatellite instability (MSI)–high tumors and how the adaptive expression of T-cell checkpoints makes these tumors sensitive to immunotherapy. But importantly it was also evidence that predictive biomarkers are critical to target a population of cancer patients for immunotherapy.
A: (Nicolas J. Llosa) There is an immense need to better understand appropriate clinical trial design, clinical trial endpoints, and the molecular and cellular events leading to tumor rejection or resistance to immuno-oncology in patients with colon cancer. To that end, we examined the immune tumor microenvironment of MSS and MSI-high colon cancer specimens and defined the main mechanisms of immune evasion in those two groups.
Q: What surprised or excited you most about the findings?
A: (Franck Housseau) It remains exciting that the study of one responding colorectal patient who was the only one among about fifty other patients who did not respond to PD-1 blockade was able to provide a scientific rationale to open an agnostic biomarker clinical trial with the success we now know. Our work provided the scientific rationale for the clinical trial that led to the approval of pembrolizumab in the treatment of MSI-positive cancer, which had such a big impact for the treatment of colorectal cancer.
A: (Nicolas J. Llosa) Our findings had an immediate impact since we discovered that MSI-positive tumors have a “hot” immune microenvironment presaging the first tissue-agnostic FDA approval, for pembrolizumab in unresectable or metastatic, MSI-high or mismatch repair–deficient solid tumors.
Q: What has been the paper’s greatest impact in the years that followed?
A: (Franck Housseau) Immune checkpoint blockade provided new therapeutic solutions for patients with advanced colorectal cancer, whose overall survival had previously been so short.
A: (Nicolas J. Llosa) Our work has provided a framework for high-impact studies over the years, integrating immunology, oncology, and genomics to understand the diversity of the tumor microenvironment in colon cancer, which can be exploited for designing new combinatorial immunotherapies.