The Prevalence of Cancer-Associated Autoantibodies in Patients with Gastric Cancer and Progressive Grades of Premalignant Lesions

Abstract

Serum autoantibodies against tumor-associated antigens (TAAs) are detectable in early-stage gastric cancer patients; however, the time point during cancerogenesis when they appear in circulation is still obscure. In this study, we developed a recombinant antigen microarray and analyzed the prevalence of autoantibodies against 102 TAAs in 829 gastric cancer patients and 929 healthy controls from Caucasian and Asian populations, as well as 100 patients with chronic atrophic gastritis and 775 individuals staged according to different grades of intestinal metaplasia. Six antigens, including CTAG1B/CTAG2, DDX53, IGF2BP2, TP53, and MAGEA3, were predominantly reacting with sera from gastric cancer patients when compared with healthy controls, and the seroreactivity was associated with intestinal-type gastric cancer, but not with patients' status, grade, age, gender, or stage of gastric cancer. We detected gastric cancer-associated seroreactivity in 13% of patients with advanced/severe intestinal metaplasia, which was increased in comparison with mild/moderate intestinal metaplasia (5.3%) and was comparable with that seen in early-stage gastric cancer patients (12%). Moreover, by testing serum samples taken 1 to 9 years before the clinical diagnosis of 18 incident gastric cancer cases, we detected autoantibody responses against several TAAs-SOX2, MYC, BIRC5, IGF2BP1, and MUC1. Our results suggest that humoral immune response against TAAs is generated already during premalignant stages. Based on the obtained results, cancer-associated autoantibodies might make a valuable contribution to the stratification of high-risk patients with premalignant lesions in the stomach through enhancing the positive predictive power of existing risk models. .

Using recursive partitioning approach to select tumor‐associated antigens in immunodiagnosis of gastric adenocarcinoma

“…Zayakin et al reported that a 45‐autoantibody signature could discriminate GC and healthy controls with AUC of 0.79 (59% sensitivity and 90% specificity) and could detect early GC with equal sensitivity as advanced GC (however, the P ‐value they showed was 0.09) . Meistere et al reported that six antigens of CTAG1B/CTAG2, DDX53, IGF2BP2, TP53, and MAGEA3 were predominantly reacting with sera from GC patients when compared with healthy controls, and that the seroreactivity was associated with intestinal‐type GC, but not with stage. Comparatively, our results suggested that the nine TAA as a panel may have the potential to distinguish GAC patients from normal individuals.…”

“…Werner et al40 reported that a combination of five autoantibodies to MAGEA4, CTAG1, TP53, ERBB2_C and SDCCAG8 could detect 32% of GC patients at a specificity of 87%, and also showed no difference between early stage and late stage.Zayakin et al reported that a 45-autoantibody signature could discriminate GC and healthy controls with AUC of 0.79 (59% sensitivity and 90% specificity) and could detect early GC with equal sensitivity as advanced GC (however, the P-value they showed was 0.09) 41. Meistere et al42 reported that six antigens of CTAG1B/…”

Antigen Specificity and Clinical Significance of IgG and IgA Autoantibodies Produced in situ by Tumor-Infiltrating B Cells in Breast Cancer

“…For the production of antigen array, cDNA fragments encoding 91 antigens were cloned into the pFN19A (HaloTag®7) T7 SP6 Flexi bacterial expression vector (Promega, USA) as described before ( 24 ). A His-tag coding sequence was introduced upstream the Halo-tag and the cDNAs encoding the antigens were inserted at the 3′ end of the Halo tag.…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…It has become evident that intact and balanced microbiota, on its own merit, has a positive impact on the health and physiology of the host by influencing a variety of biological functions ranging from behavior, to obesity and cancer (217). Indeed, the microbiome has been dubbed as a "key orchestrator of cancer therapy, " modulating chemotherapy, radiotherapy and immunotherapy ↓ Anti-tumor Th1 (IL12A, GZMB) ↑ Pro-tumorigenic Th2 ↑ Pro-inflammatory cytokines (IL-6, TNF-α) in AAH (190,191) ↓ Anti-tumor Th1 (IL12A) ↑ Pro-tumorigenic Th2 ↑ Immune suppressive mechanisms (IL6, IL10) (191,192) ↑ Immune checkpoints (PD-L2, LAG-3) in Lynch syndrome (193) ↑ Immune checkpoints (CTLA-4, CCR2) (191) ↑ Immune checkpoints (PD-1, CTLA−4, VISTA, LAG−3, TIM-3) (191) ↑ CD4+ and CD8+ TILs (194) ↑ Exhausted CD8+ TILs reactive to neoantigens (195) ↓ Cell-mediated immune response (195) Uncontrolled TLR signaling (196,197) ↑ TLR and inflammatory mediators (NF-κB) ↑ downstream chemokines (IL-6, IL−17) (198) ↓ TLR, ↓ Effector cytokine production (IFN-γ, TNF-α) (199) Progressive infiltration of innate immunosuppressive cells and M2 macrophages and T regs in OPLs (188,200) Immature macrophage-lineage cell infiltration (201) Massive tumor immune cell infiltration (201) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (202) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) ↑ B-cell chemotaxis (↑ CXCL13, CXCL14) (191) Common tumor antigens between cancers and PMLs (203) ↑ Neoantigen expression in due to infiltration of CD4+ and CD8+ T cell as well as ↑ PD-1 (179) ↑ Immunogenic neoantigen load activating anti-tumor T cell response (195) Humoral cell-mediated immune response activated against TAA in gastric premalignant lesions (204) Activation of cell-mediated immune response and recognition of neoepitopes (179) Activation of cell-mediated immune response and recognition of neoepitopes (179) Very few chromosomal mutations (TP53 in Barret's esophagus) …”