Infiltration of Lynch colorectal 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(-)/GZMB(+) cell population.

RESULTS: We discovered that high tumor infiltration by activated CD8(+) T cells correlated with aberrant HLA class I expression and associated with early tumor stages (P < 0.05). CD8(+) T cells were most abundant in HLA class I heterogeneous tumors (P = 0.02) and frequent in HLA class I-negative cases (P = 0.04) when compared with HLA class I-positive carcinomas. An elusive immune cell population (CD45(+)/CD8(-)/CD56(-)/GZMB(+)) 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 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.