Immunoselection by T lymphocytes generates repeated MHC class I-deficient metastatic tumor variants

Abstract

Alteration of MHC class I molecule expression is a widespread mechanism used by tumor cells to evade T cell responses. It has long been proposed that the origin of these MHC class I-negative or -deficient tumor variants is T cell immune selection. However, there are no experimental or clinical data to substantiate this hypothesis, and this issue is currently the subject of debate. Here we report that an H-2 class I-negative fibrosarcoma tumor clone generated MHC class I-negative spontaneous lung metastases in immunocompetent syngeneic BALB/c mice. Interestingly, the same B9 clone generated MHC class I-positive metastatic nodes, under basal conditions, in athymic nu/nu BALB/c mice. This phenomenon was observed in the metastatic nodules generated after a period of in vivo growth but not in the primary tumors growing locally in the footpad. These findings support the hypothesis that the H-2 phenotype of metastatic nodes is influenced by the T cell repertoire of the host, since in the absence of this T cell pressure (i.e., in nude mice) the metastatic nodes 'recovered' H-2 class I expression. In addition, 2 different phenotypes were found when the metastatic nodules obtained from immunocompetent mice were treated with IFN-␥. One phenotype, present in 83% of the colonies, was characterized by resistance of the L d molecule to IFN-␥ induction, due to a deletion involving the L d gene. The second phenotype (17% of the colonies) was similar to the original B9 clone and was characterized by the response of K, D and L class I genes to IFN-␥. These data provide evidence that the changes in MHC class I expression during tumor development might not be random but could be predictable.

High frequency of HLA-B44 allelic losses in human solid tumors

“…These variant clones can escape specific T-cell responses and acquire new properties that allow them to invade and metastasize. Evidence obtained recently in experimental tumor systems supports this hypothesis [7].…”

“…Differences in HLA class I allelic expression have been found in the presence of proteosome inhibitors [30] and in situations when invariant chain is expressed [31]. In this connection, alterations in HLA class I molecule expression can be considered an epiphenomenon of the process of malignant transformation, and thus as a marker of tumor clonality and immune selection [7,8].…”

“…The HLA-B44 negative tumor variants may be selected through the antitumoral T-cell immune response against HLA-B44 positive tumor cells. Some studies have found evidence of immune selection of tumor cell variants that lose MHC class I expression in experimental and human tumors [7,8,36], particularly after immunotherapy [37,38]. This would further imply that other alleles such as HLA-A2, whose expression within the same tumor is maintained, present weakly immunogenic peptides.…”

Complete loss of HLA class I antigen expression on melanoma cells: A result of successive mutational events

“…These experimental data contribute to the theory that the selection of tumor variants with altered MHC expression might be the result of a T cell-dependent process. 27 In addition to the total loss of HLA class I expression, other escape mechanisms might have contributed to the aggressive metastatic behavior of the tumor in patient UKRV-Mel-2. CTLs mediate tumor cell killing in either a Fas-or a perforin-dependent manner.…”

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

“…4). The immunoselection hypothesis has been supported by the increased frequency of HLA class I antigen presentation defects observed in tumors upon application of T cell-based immune therapies (5,6). Different mechanisms may eventually lead to impairments of HLA class I antigen presentation (7).…”