Colorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major... Show moreColorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major role in shaping the immune landscape of tumors and in determining the clinical response of colorectal cancer patients to immune checkpoint blockade therapies. Colorectal cancers that develop in a context of DNA mismatch repair or polymerase proofreading deficiency are generally conspicuously infiltrated by effector memory T cells and are associated with an improved clinical prognosis relative to their replication repair-proficient counterpart. While mismatch repair-deficient colorectal cancers, and most likely POLE and POLD1-mutated cancers, are amenable to immune checkpoint blockade therapies, the promise of immunotherapy still remains unfulfilled for for the majority of colorectal cancer patients. This review focusses on the role of the immune system in the tumorigenesis and clinical behavior of colorectal cancer. Furthermore, we discuss how latest advances in the fields of genomics and oncoimmunology may pave the way to broaden the scope of immunotherapy for this disease. Show less
In this thesis, we studied some of the genetic and molecular alterations that accompany the tumorigenesis of mismatch repair (MMR) and MUTYH deficient colorectal cancers, with focus on immune... Show moreIn this thesis, we studied some of the genetic and molecular alterations that accompany the tumorigenesis of mismatch repair (MMR) and MUTYH deficient colorectal cancers, with focus on immune escape mechanisms. We discovered that loss of Human Leukocyte Antigen (HLA) class I expression was more frequent in those tumors than in the remaining spectrum of colorectal cancers (CRCs), and that distinct genetic mechanisms explained HLA class I abrogation in sporadic and hereditary mismatch repair deficient tumors. We then explored a potential association between the magnitude and quality of lymphocytic infiltration with the tumors__ HLA class I phenotypes and clinicopathological stages in a cohort of Lynch CRCs. Higher lymphocytic infiltration, particularly of cytotoxic lymphocytes, was observed in cancers presenting HLA class I defects and in tumors diagnosed at earlier stages, thus, supporting the role of the immune system in selecting immune evasive tumor traits and in counteracting cancer progression. Finally, we functionally characterized one of the most common genetic alterations that occur in MMR deficient CRCs. We demonstrated that TGFbeta signalling is active in these tumors and that TGFbeta activation occurs in a TGFBR2-dependent manner, despite the presence of truncating biallelic mutations in its gene in the majority of MMR deficient tumors. Show less
