Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy

Abstract

Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. A number of rare paraneoplastic neurologic autoimmune diseases are strongly associated with SCLC. Most patients with such paraneoplastic syndromes harbor high titers of antibodies against neuronal proteins that are abnormally expressed in SCLC tumors. These autoantibodies may cross-react with the nervous system, possibly contributing to autoimmune disease development. Importantly, similar antibodies are present in many SCLC patients without autoimmune disease, albeit at lower titers. The timing of autoantibody development relative to cancer and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies, and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies, such as SCLC diagnosis, early detection, and therapy.

Figure 1

Association between SCLC, paraneoplastic syndromes, and (A) anti-Hu, (B) anti-voltage-gated calcium channels (VGCC), (C) anti-SOX1, and (D) anti-recoverin (Rc) autoantibodies. Arrows provide further description of distinct groups within subsections of each circle or oval (see Table 1 for references).

Figure 2

Anti-Hu reactivity relative to SCLC detection and image-based screening of SCLC-prone mice. (A) Anti-Hu reactivity was detected 40-100 days prior to clinical detection of SCLC. Graphs from the six highly positive mice are shown. The dotted line represents the date of first clinical detection of tumor by CT scan and/or luminescence detection. The titer was determined by the highest fold dilution of plasma or serum in which there was a positive Western blot signal against recombinant HuD protein. The time (in days) between the measurement of a titer above background (titer > 5000) and clinical detection is indicated by a horizontal bar. SCLC tumor was not detected in mouse 489556, though the mouse became very sick. Mouse 509631 was sacrificed at the time of high titer detection, and the lungs of this animal showed neuroendocrine lesions in situ, but cancer was not detected. Crosses indicate dates of sacrifice. Titer values are in thousands. (B-E) Mice carrying homozygously floxed p53 and Rb alleles, as well as a luciferase reporter under the control of a β-actin promoter, were infected with adenovirus carrying the Cre recombinase gene via intratracheal instillation. Mice were monitored for tumor formation using bioluminescence detection (B, C, left panels, and D), X-ray based CT-scan (B and C, right panels, open circles, heart; arrowheads, tumor mass), and clinical symptoms like weight loss (E), altered coat, or kyphosis. B-E show the follow up of mouse 484305 which showed anti-Hu reactivity with a titer of 80,000 at 180 days (arrows) after Adeno-Cre infection. At that time, tumor was undetectable by imaging techniques (images taken 203 and 256 days after Adeno-Cre infection) (B). Tumor became detectable 256 days after Adeno-Cre infection (C). Acute weight loss was observed 286 days after Adeno-Cre infection (E). (Reprinted from [48], with permission from Elsevier, License Number 2460341062344).