SOX2-specific adaptive immunity and response to immunotherapy in non-small cell lung cancer

• Authors: Kavita Dhodapkar, Emory University; Scott N. Gettinger, Yale University; Rituparna Das, Yale University; Henry Zebroski, Rockefeller University; Madhav Dhodapkar, Emory University
• Journal Title: OncoImmunology
• Volume: Volume 2, Number 7
• Publisher: Taylor & Francis: STM, Behavioural Science and Public Health Titles | 2013-07-01, Pages e25205-e25205
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.4161/onci.25205
• Subjects: Health Sciences, Immunology; Health Sciences, Oncology; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Immunology; sox2; embryonal stem cells; lung cancer; programmed death 1; immunotherapy; checkpoint blockade; STEM-CELLS; SOX2; ANTIBODY; ADENOCARCINOMA; ONCOGENE; ANTIGENS; SURVIVAL; SAFETY

Abstract

Immunotherapeutic strategies including the blockade of programmed death 1 (PD-1) receptors hold promise for the treatment of various cancers including non-small cell lung carcinoma (NSC LC). Preclinical data suggest that pre-existing tumor immunity is important for disease regression upon checkpoint blockade-based therapies. However, the nature of antigen-specific T-cell responses that correlate with the clinical response to immunotherapy in NSC LC patients is not known. The embryonic stem cell gene SRY (sex determining region Y)-box 2 (SOX2) has recently emerged as a major oncogenic driver in NSC LC. Here, we show that nearly 50% of a cohort of NSC LC patients mounted both CD4+ and CD8+ T-cell responses against SOX2, which could be readily detected among peripheral blood mononuclear cells. T-cell responses against SOX2 were associated with NSC LC regression upon immunotherapy with anti-PD-1 monoclonal antibodies, whereas none of the patients lacking SOX2-specific T cells experienced disease regression following immune checkpoint blockade. Conversely, cellular and humoral responses against viral antigens or another tumor-associated antigen (NYES O-1)failed to correlate with the clinical response of NSC LC patients to immunotherapy. Of note, the administration of PD-1-blocking antibodies was associated with intramolecular epitope spread as well as with the amplification of SOX2- specific immune responses in vivo. These findings identify SOX2 as an important tumor-associated antigen in NSC LC and link the presence of SOX2-specific T cells with the clinical response of lung cancer patients to immunotherapy.