Besides being expressed on professional antigen-presenting cells, HLA
class II antigens are expressed on various
tumors of non-lymphoid origin, including a subset of
colorectal cancers (CRC). Information about the regulation of HLA
class II antigen expression is important for a better understanding of their role in the interactions between
tumor and immune cells. Whether lack of HLA
class II antigen expression in
tumors reflects the selective immune destruction of HLA
class II antigen-expressing
tumor cells is unknown. To address this question, we tested whether lack of HLA
class II antigen expression in CRC was associated with immune cell infiltration. We selected microsatellite-unstable (MSI-H) CRC, because they show pronounced
tumor antigen-specific immune responses and, in a subset of
tumors, lack of HLA
class II antigen expression due to mutations inactivating HLA class II-regulatory genes. We examined HLA
class II antigen expression, mutations in regulatory genes, and CD4-positive T cell infiltration in 69 MSI-H CRC lesions. Mutations in RFX5, CIITA, and RFXAP were found in 13 (28.9%), 3 (6.7%), and 1 (2.2%) out of 45 HLA
class II antigen-negative
tumors. CD4-positive tumor-infiltrating lymphocyte counts were significantly higher in HLA
class II antigen-negative
tumors harboring mutations in HLA class II-regulatory genes (107.4 T cells per 0.25 mm(2)) compared to
tumors without mutations (55.5 T cells per 0.25 mm(2), p = 0.008). Our results suggest that the outgrowth of
tumor cells lacking HLA
class II antigen expression due to mutations of regulatory genes is favored in an environment of dense CD4-positive T cell infiltration.