SOX2-specific adaptive immunity and response to immunotherapy in non-small celllung cancer.

摘要

Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-smallcell lung carcinoma (NSCLC). Preclinical data suggest that pre-existing tumorimmunity is important for disease regression upon checkpoint blockade-basedtherapies. However, the nature of antigen-specific T-cell responses thatcorrelate with the clinical response to immunotherapy in NSCLC patients is notknown. The embryonic stem cell gene SRY (sex determining region Y)-box 2 (SOX2)has recently emerged as a major oncogenic driver in NSCLC. Here, we show thatnearly 50% of a cohort of NSCLC patients mounted both CD4(+) and CD8(+) T-cellresponses against SOX2, which could be readily detected among peripheral bloodmononuclear cells. T-cell responses against SOX2 were associated with NSCLCregression upon immunotherapy with anti-PD-1 monoclonal antibodies, whereas none of the patients lacking SOX2-specific T cells experienced disease regressionfollowing immune checkpoint blockade. Conversely, cellular and humoral responses against viral antigens or another tumor-associated antigen (NY-ESO-1) failed tocorrelate with the clinical response of NSCLC patients to immunotherapy. Of note,the administration of PD-1-blocking antibodies was associated with intramolecularepitope spread as well as with the amplification of SOX2-specific immuneresponses in vivo. These findings identify SOX2 as an important tumor-associated antigen in NSCLC and link the presence of SOX2-specific T cells with the clinicalresponse of lung cancer patients to immunotherapy.