Seminar: Cancer Epigenetics | February 9 | 11 a.m.-12 p.m. | Auditorium FCiências.ID (FCUL C1)
Sergio Alonso, Cancer Genetics and Epigenetics (CGE), Translational Program in Cancer Research (CARE), Germans Trias i Pujol Research Institute (IGTP)
Epigenomic alterations associated to tumor-infiltrating lymphocytes in colorectal cancer
Host: Federico Herrera
Sponsored by:
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Financed by national funds thought FCT – Fundação para a Ciência e a Tecnologia, I.P., under the following project references: UIDB/04046/2020 and UIDP/04046/2020
One of the most successful immunotherapies developed in the last decade involves the use of monoclonal antibodies that inactivate immune checkpoint proteins, thus releasing the immune response against cancer cells. Tumor-infiltrating lymphocytes (TILs) are essential for a successful response to this therapy. Tumors with high T-cell infiltration (hot tumors) tend to respond better than tumors with low T-cell infiltration (cold tumors). Most clinical trials evaluating the efficacy of immunotherapy in colorectal cancer are currently focused on a subtype of hypermutant tumors, which are generally highly immunogenic. However, these tumors represent only about 15% of all colorectal cancers, limiting the application of this therapy to just a minority of colorectal cancer patients. Importantly, the relationship between the number of mutations and lymphocytic infiltration is not straightforward: about 25% of hypermutant colorectal cancers have low levels of lymphocytic infiltration and, conversely, almost 50% of non-hypermutant colorectal tumors have high levels of lymphocytic infiltration. Therefore, the number of mutations, while important, is not the only factor influencing lymphocytic infiltration. Some mutations might be poorly immunogenic, some tumors might use unknown mechanisms to evade lymphocytic recognition, and both the tumor microenvironment and the overall immune status of the patient may also play a crucial role in tumor recognition by immune cells. Identifying these factors is essential to improve the efficacy of immunotherapy, particularly if these factors are actionable.
We have investigated epigenomic alterations associated with TILs in colorectal cancer. I will present our most recent data showing that certain extracellular matrix remodelers become epigenetically silenced in a coordinated manner in non-hypermutant CRCs, and that this epigenetic silencing is associated with higher levels of tumor-infiltrating lymphocytes. Therefore, inhibiting these extracellular matrix remodelers with specific drugs may help the immune system recognize tumor neoantigens and increase tumor lymphocytic infiltration, making these non-hypermutant CRCs more receptive to subsequent immune checkpoint inhibitor therapy.