Data from Infiltration of Lynch Colorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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<sup>−</sup>/CD8<sup>−</sup>/GZMB<sup>+</sup> cell population.</p><p><b>Results:</b> We discovered that high tumor infiltration by activated CD8<sup>+</sup> T cells correlated with aberrant HLA class I expression and associated with early tumor stages (<i>P</i> < 0.05). CD8<sup>+</sup> T cells were most abundant in HLA class I heterogeneous tumors (<i>P</i> = 0.02) and frequent in HLA class I–negative cases (<i>P</i> = 0.04) when compared with HLA class I–positive carcinomas. An elusive immune cell population (CD45<sup>+</sup>/CD8<sup>−</sup>/CD56<sup>−</sup>/GZMB<sup>+</sup>) was characteristic for HLA class I–negative tumors lacking lymph node metastases (<i>P</i> < 0.01).</p><p><b>Conclusions:</b> The immune system assumes an important role in counteracting the progression of Lynch colorectal cancers and in selecting abnormal HLA class I phenotypes. Our findings support the development of clinical strategies that explore the natural antitumor immune responses occurring in Lynch syndrome carriers. <i>Clin Cancer Res; 18(5); 1237–45. ©2012 AACR</i>.</p></div>