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. In order 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 clinicopathological stage. Experimental Design: HLA class I expression was assessed by means of immunohistochemistry. Characterization of tumor-infiltrating lymphocytes was carried-out by employing a triple immunofluorescence procedure that allowed the simultaneous detection of CD3, CD8 and granzyme B (GZMB) positive cells. Additional markers were also employed 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 < .05). CD8+ T-cells were most abundant in HLA class I heterogeneous tumors (P = .02) and frequent in HLA class I negative cases (P = .04), when compared to 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 < .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 host's natural anti-tumor immune responses.
- Received August 3, 2011.
- Revision received December 5, 2011.
- Accepted December 23, 2011.
- Copyright © 2012, American Association for Cancer Research.