Immunotherapy is a rising star in the fight against cancer and works by taking off the brakes of the
patient’s own immune system so it can attack cancer more efficiently. While spectacular
responses have been observed in some patients, the majority has little or no reaction to
immunotherapy. However, a subset of tumors that are very responsive to these drugs has now
been unveiled, namely mismatch repair-deficient (dMMR) tumors. The particular changes in the
DNA of dMMR tumors tags them with ‘red flags' –being like a red rag to a bull– calling attention
for the unleashed immune system to attack them. Still, half of patients with dMMR tumors will not
respond. If we can identify ways to overcome immunosuppressive mechanisms within dMMR
tumors, we can harness the full potential of immunotherapy in this already promising subset of
tumors. I hypothesize that the origin of this resistance lies not within the cancer cells themselves,
but in the cancer-associated fibroblasts (CAFs). CAFs constitute a very abundant cell type in dMMR
tumors. Basically, CAFs act as a supply line providing the necessary chemical signals to help cancer
cells survive. My research proposal is aimed at understanding the role of CAFs in resistance to
immunotherapy in these potentially highly immunoresponsive tumors. Furthermore, rather than
simply targeting cancer cells, targeting of the supply line –CAFs– is proposed, since once the
supplies are cut off, cancer cells might be unable to resist immunotherapy.