PURPOSE:Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in ovarian cancer patients undergoing standard treatment.EXPERIMENTAL DESIGN:Tumor-associated T cells from three ovarian cancer patients were assessed by ELISPOT for recognition of non-synonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence. RESULTS:The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however a highly specific CD... More
PURPOSE:Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in ovarian cancer patients undergoing standard treatment.EXPERIMENTAL DESIGN:Tumor-associated T cells from three ovarian cancer patients were assessed by ELISPOT for recognition of non-synonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence. RESULTS:The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however a highly specific CD8+ T cell response to the mutation HSDL1L25V was detected in one patient. In the primary tumor, the HSDL1L25V mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1L25V-specific CD8+ T cell response. At second recurrence, the HSDL1L25V mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.CONCLUSIONS:The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, transient and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy.
