T-cell dependent immunoselection.

In a recent issue of Nature, two groups describe the process of cancer immunoediting whereby an individual is protected from cancer though the elimination and immunogenic modification of cancer cells. Matsushita and colleagues use whole-exon sequencing of chemically induced mouse sarcomas to obtain evidence for T cell-mediated immunoselection. The authors characterized mutations in immunodeficient mice and thereby elegantly identified a tumor rejection antigen. Further it was demonstrated that T cell-dependent immunoselection is a crucial mechanism underlying the outgrowth of tumor cells. This exciting study was published alongside a study from DuPage et al., demonstrating that immunosurveillance and immunoediting can occur in an oncogene-driven endogenous tumor model provided that the tumors carry strong neo-antigens that are not present in the host. DuPage and colleagues showed that loss of tumor antigen expression or presentation on Class I MHC molecules was necessary and sufficient for immunoediting to occur. These exciting animal studies highlight the importance of tumor-specific (mutated) antigens and illustrate the importance of T cells in the immunoselection process. Such approaches may facilitate the development of individualized cancer immunotherapies directed against patient-specific mutated tumor antigens. This is intriguing since only a few commonly shared mutated T-cell antigens have been described, e.g., mutated BRAF, and RAS. Much focus has been recently on the constitutively activating V600E BRAF mutation in melanoma due to the approval of a specific BRAF inhibitor (vemurafenib) to treat BRAFV600E-positive melanoma. A few years ago, both spontaneous CD8+ and CD4+ T-cell responses was described against the V600E mutation in melanoma patients., These responses were mutation specific as the corresponding epitopes derived from wild type BRAF were not recognized by the T cells. Even more noteworthy, however, was the observation that in two of the patients carrying BRAFV600E-positive primary tumors, the V600E mutation could not be detected in any of the evolving metastases. The expression of mutant BRAF is important for the maintenance of the malignant phenotype. Thus, the loss of BRAFV600E during disease development suggested an active immunoselection of melanoma cells with a wild type BRAF genotype. A similar observation was made in another study describing HLA-A2-restricted T-cell responses against the V600E mutation in melanoma patients. Although these clinical observations only are of anecdotal character, they suggest that the loss of the mutated BRAF genotype during the progression from primary to metastatic disease in melanoma patients exhibiting BRAFV600E-specific T-cell responses is caused by an active immunoselection of non-mutated melanoma by the host, especially in light of the recent publication in Nature. Taken together, these findings underline the potential of truly tumor-specific antigens for cancer immunotherapy.