Abstract:Although tumor infiltrating lymphocyte (TIL) density is prognostic and predictive in colorectal cancer (CRC), the impact of tumor genetics upon colorectal immunobiology is unclear. Identification of genetic factors that influence the tumor immunophenotype is essential to improve the effectiveness of stratified immunotherapy approaches. We carried out a bioinformatics analysis of CRC data in The Cancer Genome Atlas (TCGA) involving two-dimensional hierarchical clustering to define an immune signature that we us… Show more
“…PD-L1 expression have frequently been observed in MSI tumors with strong correlation to high levels of CD3 and CD8 positive cells. 12,14,28–30 In line with our results, PD-L1 expression are more frequently observed on immune cells at the invasive margin and rarely observed on tumor cells. 11,14,31 PD-L1 has been detected as a soluble ligand and may potentially be secreted by MMR deficient tumor cells.…”
Section: Discussionsupporting
confidence: 91%
“…Up-regulation of PD-L1 has been linked to MSI tumors, and based on our data, to Lynch syndrome tumors. 11,14,28,29,31 10.1080/2162402X.2018.1515612-F0003Figure 3.Hypothesized model showing the development of two different immune evasion mechanisms in Lynch syndrome-associated colorectal cancer. When the baseline epithelial tissue is highly infiltrated with CD3 and CD8 T cells (in purple) (panel to the right), preliminary tumor cells (in green) are forced to evade the immune system at early stages.…”
Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.
“…PD-L1 expression have frequently been observed in MSI tumors with strong correlation to high levels of CD3 and CD8 positive cells. 12,14,28–30 In line with our results, PD-L1 expression are more frequently observed on immune cells at the invasive margin and rarely observed on tumor cells. 11,14,31 PD-L1 has been detected as a soluble ligand and may potentially be secreted by MMR deficient tumor cells.…”
Section: Discussionsupporting
confidence: 91%
“…Up-regulation of PD-L1 has been linked to MSI tumors, and based on our data, to Lynch syndrome tumors. 11,14,28,29,31 10.1080/2162402X.2018.1515612-F0003Figure 3.Hypothesized model showing the development of two different immune evasion mechanisms in Lynch syndrome-associated colorectal cancer. When the baseline epithelial tissue is highly infiltrated with CD3 and CD8 T cells (in purple) (panel to the right), preliminary tumor cells (in green) are forced to evade the immune system at early stages.…”
Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.
“…On the other hand, CRC patients with RAS mutant tumors had significantly lower expression of a coordinated immune response, a fact that could be translated into unsuccessful immunological therapies (42).…”
Section: Immune Response and Correlation With Clinicopathological Facmentioning
The importance of host immune response in colorectal cancer (CRC) has been constantly revealed through the last 10 years. A number of relevant immune markers have been introduced as prognostic and are now been used alone or in combination with each other in clinical practice. Efforts establishing a worldwide consensus on the implications of immune-profiles in conjunction to other factors are designed in the right direction in order to more effectively categorize patients with CRC in groups that might benefit from currently used or future applied therapies. On the other hand, a number of clinical trials have evolved the application of immunotherapies in patients with CRC both in the adjuvant and palliative setting.
“…Techniques for categorizing these features, including IHC staining and gene expression (2,(4)(5)(6)(8)(9)(10)(11)(12), have been extensively studied, but functional studies on tumors and infiltrating leukocytes are also of interest. In an initial retrospective IHC analysis evaluating the prognostic relationship between tumor-infiltrating lymphocytes and clinical outcomes in early-stage disease, Galon and colleagues identified a correlation between recurrence-free survival and the density of infiltrating CD3 þ CD8 þ lymphocytes at the tumor margin and center.…”
Section: Features Associated With Improved Immune Responsivenessmentioning
confidence: 99%
“…However, few objective responses are seen in unselected colorectal cancer patients (2,3). Observations that mutational load correlates with immune response to checkpoint blockade in many malignancies led to studies of checkpoint blockade in patients with advanced colorectal cancer (4).…”
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