RESUMEN
Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQ) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients.Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T-cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events.Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration.Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune cell infiltration within a subgroup of prostate cancer patients. Clin Cancer Res; 23(24); 7596-607. ©2017 AACR.
Asunto(s)
Epítopos de Linfocito T/genética , Antígeno HLA-A2/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/inmunología , Secuencia de Aminoácidos/genética , Linfocitos T CD8-positivos/inmunología , Análisis Mutacional de ADN , Epítopos de Linfocito T/inmunología , Genes MHC Clase I/genética , Genes MHC Clase I/inmunología , Antígeno HLA-A2/inmunología , Humanos , Masculino , Proteínas de Fusión Oncogénica/inmunología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Unión Proteica , Linfocitos T/inmunologíaRESUMEN
Prostate cancer patients often receive androgen deprivation therapy (ADT) in combination with radiation therapy (RT). Recent evidence suggests that both ADT and RT have immune modulatory properties. First, ADT can cause inï¬ltration of lymphocytes into the prostate, although it remains unclear whether the inï¬ux of lymphocytes is beneï¬cial, particularly with the advent of new classes of androgen blockers. Second, in rare cases, radiation can elicit immune responses that mediate regression of metastatic lesions lying outside the ï¬eld of radiation, a phenomenon known as the abscopal response. In light of these ï¬ndings, there is emerging interest in exploiting any potential synergy between ADT, RT, and immunotherapy. Here, we provide a comprehensive review of the rationale behind combining immunotherapy with ADT and RT for the treatment of prostate cancer, including an examination of the current clinical trials that employ this combination. The reported outcomes of several trials demonstrate the promise of this combination strategy; however, further scrutiny is needed to elucidate how these standard therapies interact with immune modulators. In addition, we discuss the importance of synchronizing immune modulation relative to ADT and RT, and provide insight into elements that may impact the ability to achieve maximum synergy between these treatments.
