Autologous anti-SOX2 antibody responses reflect intensity but not frequency of antigen expression in small cell lung cancer

Abstract

BackgroundAnti-SOX2 antibody responses are observed in about 10 to 20% of small cell lung cancer (SCLC) patients. The aim of this study was to determine whether such responses reflect a particular pattern of SOX2 protein expression in the tumor and whether this pattern associates with clinical outcome.MethodsParaffin embedded tumor tissues, obtained from SCLC patients who had no evidence of paraneoplastic autoimmune degeneration, were evaluated for SOX2 expression by immunohistochemistry for both intensity and extent of staining. Sera from the same patients were tested for autologous antibodies against recombinant SOX2 by enzyme-linked immunosorbent assay (ELISA). Correlates between overall survival and various clinical parameters including SOX2 staining and serology were determined.ResultsSOX2 protein expression was observed in tumor tissue in 89% of patients. Seventeen patients (29%) were seropositive for SOX2 antibodies and, in contrast to SOX2 staining, the presence of antibody correlated with limited disease stage (p = 0.05). SOX2 seropositivity showed a significant association with the intensity of SOX2 staining in the tumor (p = 0.02) but not with the frequency of SOX2 expressing cells.ConclusionAnti-SOX2 antibodies associate with better prognosis (limited stage disease) while SOX2 protein expression does not; similar to reports from some earlier studies. Our data provides an explanation for this seemingly contrasting data for the first time as SOX2 antibodies can be observed in patients whose tumors contain relatively few but strongly staining cells, thus supporting the possible presence of active immune-surveillance and immune-editing targeting SOX2 protein in this tumor type.

Assessment of neuronal autoantibodies in patients with small cell lung cancer treated with chemotherapy with or without ipilimumab

“…In patients with anti-Yo related PNS, antibody titers decreased after surgical removal of the tumor without resolution of the neurological symptoms. 54,55 Overall NAA levels appear to decrease following removal of tumor antigen; the observation of worsening PNS with disease recurrence 32,56 and increase risk of relapse in HPVC patients whose HPV antibodies persist 57 both support this conclusion. Whether levels of NAA are important clinically or simply 'bystanders' of cellular immune consequences of treatment is uncertain.…”

“…30 Consistent with these observations and in line with previous evidence, 53% of our patients had detectable levels of at least one NAA and none had neurological symptoms. 22,[28][29][30][31][32][33] All but one patient with positive detection of anti-HuD, showed lower titers of NAAs in comparison with the patient with known anti-HuD related PNS (positive control) (data not shown). Consistent with previously reported series, 22,30 in the current study anti-Sox1 was the most prevalent tumor-associated NAA.…”

“…The presence of NAAs has been linked to early stages and in turn to better outcome. 28,29,32,39 The concomitant cytotoxic T cell response 27,[40][41][42] might contribute to a degree of tumor control, sparing the immune privileged nervous system. 43,44 In the case of SCLC-associated PNS, the diagnosis of the neurological disease often antedates that of the tumor, 20,45 suggesting that the immune system is able to detect the presence of SCLC before the cancer develops metastases.…”

Immune evasion by cancer stem cells

“…Antibodies against another stemness transcription factor, sex-determining region Y- box 2 (SOX2), were also found in the serum of patients with lung cancer, prostate cancer, and glioblastoma [ 58 , 59 ]. The presence of SOX2-reactive antibodies predicted a good prognosis in patients with lung cancer [ 58 ].…”

“…Antibodies against another stemness transcription factor, sex-determining region Y- box 2 (SOX2), were also found in the serum of patients with lung cancer, prostate cancer, and glioblastoma [ 58 , 59 ]. The presence of SOX2-reactive antibodies predicted a good prognosis in patients with lung cancer [ 58 ]. SOX2-reactive T cells were also found in patients with monoclonal gammopathy, a benign disease, that sporadically progresses to multiple myeloma [ 60 ].…”