Strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer. the use of immunotherapy. Although immunotherapy is not yet routinely used in colorectal cancer, we now know that most treatments used (chemotherapy and biotherapy) have immunomodulatory effects, such as induction of immunogenic cell death by chemotherapy, inhibition of immunosuppression by antiangiogenic agents, and antibody-dependent cytotoxicity induced by cetuximab. Finally, many immunotherapy strategies are being developed and tested in phase?I?to III clinical trials. The most promising strategies are boosting the immune system with 1353858-99-7 cytokines, inhibition of immunoregulatory checkpoints, vaccination with vectorized antigens, and adoptive cell therapy. Comprehension of antitumor immune response and combination of the different approaches of immunotherapy may allow the use of effective immunotherapy for treatment of colorectal cancer in the near future. 0.001 for all comparisons). In multivariate analysis, the density of CD45RO+ cells was still an independent prognostic 1353858-99-7 factor. Based on these results, an immune score based on immunostaining has been elaborated, considering 4 densities: density of CD8+ T infiltrates in the center of the tumor (CT), in the invasive margin (IM), and density of memory CD45RO+ cells in the CT and in the IM. This immune score was first studied in early-stage tumors (stages?I?and II). Patients with a high density of both CD8+ and CD45RO+ cells in both the CT and IM had a disease-free survival of 95.2%, compared with 25% in patients with a low density of both CD8+ and CD45RO+ cells in both regions. This immune score was validated in a cohort of 599 specimens of stage?I?to IV CRC. In this study, assessment of immune score was a better predictor of tumor recurrence (HR = 0.64; 0.001) than TNM classification. However, the immune infiltrate Rabbit Polyclonal to JNKK is highly heterogeneous in a tumor, and quantification is observer-dependent. To simplify and harmonize the quantification of immune infiltrate, automated quantification of CD3+ cells can be used. Linear quantification of lymphocytes has been shown to be predictive of disease-free-survival in multivariate analysis with very good inter-observer reproducibility. However, other teams have not confirmed these results yet and major information are lacking in this large retrospective series such as age, MSI status or the use of adjuvant therapy. Despite these promising results, there is still no immune quantification test in routine practice to use immune infiltrate to guide our therapeutic strategies. This underlines the difficulty to find a standardized and reproducible test that complies with daily practice. Such tests should be of particular interest for clinicians, especially for stage II patients for whom the indication for adjuvant treatment is more controversial. MECHANISMS OF IMMUNE SYSTEM ESCAPE IN COLORECTAL CANCER Human leukocyte antigen class I downregulation is associated with a poor prognosis Expression of Human Leukocyte Antigen class?I?(HLA-I), the human MHC, class?I?molecules is downregulated in more than 70% of colorectal tumors. In a few cases there is complete loss of HLA-I?on tumor cells. Total loss of HLA-I?mainly results from beta2-microglobulin inactivation in MSI tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Downregulation can result from loss of HLA haplotypes due to chromosomal nondisjunction or mitotic recombination, loss of HLA locus expression, or allelic loss due to point mutations or partial deletions of HLA-I?genes. The prognostic significance of HLA-I?downregulation has been reported in a large cohort of CRC cases. Tumors with low expression of HLA-I?were associated with a significantly shorter mean disease-specific survival (41 mo, 95%CI: 26-56) compared with tumors with high expression of HLA-I?(68 mo, 95%CI: 63-74). Surprisingly, patients with a tumor with complete loss of HLA-I?expression had a similar prognosis to those with high expression (mean disease-specific survival 60 mo, 95%CI: 50-69). This is possibly related to the high activity of NK cells against HLA-I-negative tumor cells. Killer inhibitory receptors, which are inhibitory receptors on NK cells, are dependent on MHC class?I, then NK cells are activated in the absence of MHC class?I. Tumor cells with downregulation but not complete loss of HLA-I?expression could therefore avoid both T-cell- and NK-cell-mediated immune surveillance, and may be associated with a poor prognosis. Induction of regulatory T cells Induction of immunosuppressive cells is a major mechanism in escape from the host immune system. Tregs are characterized by expression of CD4, CD25, and Foxp3. 1353858-99-7 In healthy individuals, role of Tregs is to prevent autoimmune disorders. In patients with cancer, Tregs could block the immune response against tumors through cytokine-dependent or cell-cell contact mechanisms. Tregs secrete immunosuppressive cytokines as IL-10 and TGF and immunosuppressive metabolites such as adenosine. The role of Tregs in cancer was first suspected from the observation of increased Tregs in peripheral blood and tumor tissue. Strong Treg infiltration of tumors is generally associated with poor clinical outcome. Elevated blood and.