Human Cancer Biology Infiltration of LynchColorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

Purpose: Lynch syndrome colorectal cancers often lose human leukocyte antigen (HLA) class I expression. The outgrowth of clones with immune evasive phenotypes is thought to be positively selected by the action of cytotoxic T cells that target HLA class I–positive cancer cells. To investigate this hypothesis, we related the type and density of tumor lymphocytic infiltrate in Lynch colorectal cancers with their HLA class I phenotype and clinicopathologic stage. Experimental Design: HLA class I expression was assessed by means of immunohistochemistry. Characterization of tumor-infiltrating lymphocytes was carried out by using a triple immunofluorescence procedure that allowed the simultaneous detection of CD3-, CD8-, and granzyme B (GZMB)-positive cells. Additional markers were also used for further characterization of an elusive CD3 /CD8 /GZMBþ cell population. Results: We discovered that high tumor infiltration by activated CD8þ T cells correlated with aberrant HLA class I expression and associated with early tumor stages (P < 0.05). CD8þ T cells were most abundant in HLA class I heterogeneous tumors (P 1⁄4 0.02) and frequent in HLA class I–negative cases (P 1⁄4 0.04) when compared with HLA class I–positive carcinomas. An elusive immune cell population (CD45þ/ CD8 /CD56 /GZMBþ) was characteristic for HLA class I–negative tumors lacking lymph node metastases (P < 0.01). Conclusions: The immune system assumes an important role in counteracting the progression of Lynch colorectal cancers and in selecting abnormalHLA class I phenotypes. Our findings support the development of clinical strategies that explore the natural antitumor immune responses occurring in Lynch syndrome carriers. Clin Cancer Res; 18(5); 1237–45. 2012 AACR.