An important role for tumor infiltrating B lymphocytes (TIL-B) in the immune response to cancer is emerging; however, very little is known about the antigen specificity of antibodies produced in situ. The presence of IgA antibodies in the tumor microenvironment has been noted although their biological functions and clinical significance are unknown. This study used a 91-antigen microarray to examine the IgG and IgA autoantibody repertoires in breast cancer (BC). Tumor and adjacent breast tissue supernatants and plasma from BC patients together with normal breast tissue supernatants and plasma from healthy controls (patients undergoing mammary reduction and healthy blood donors) were analyzed to investigate relationships between autoantibodies and the clinical, histological and immunological features of tumors. Our data show that >84% of the BC samples tested contain autoantibodies to one or more antigens on the array, with ANKRD30BL, COPS4, and CTAG1B being most frequently reactive. Ex vivo TIL-B responses were uncoupled from systemic humoral responses in the majority of cases. A comparison of autoantibody frequencies in supernatants and plasma from patients and controls identified eight antigens that elicit BC-associated autoantibody responses. The overall prevalence of IgG and IgA autoantibodies was similar and while IgG and IgA responses were not linked they did correlate with distinct clinical, pathological and immunological features. Higher levels of ex vivo IgG responses to BC-associated antigens were associated with shorter recurrence-free survival (RFS), HER2 overexpression and lower tumor-infiltrating CD8+ T cell counts. Higher IgA levels were associated with estrogen and progesterone receptor-negative cancers but were not significantly associated with RFS. Furthermore, ex vivo IgA but not IgG autoantibodies reactive to BC-associated antigens were linked with germinal center and early memory B cell maturation and the presence of tertiary lymphoid structures suggesting that these TIL-B are activated in the tumor microenvironment. Overall, our results extend the current understanding of the antigen specificity, the biological and the clinical significance of IgG and IgA autoantibodies produced by BC TIL-B in situ.

Combining different standard therapies with immunotherapy for the treatment of solid tumours has proven to yield a greater clinical benefit than when each is applied separately; however, the percentage of complete responses is still far from optimal, and there is an urgent need for improved treatment modalities. The latest literature data suggest that tertiary lymphoid structures (TLS), previously shown to correlate with the severity of autoimmune diseases or transplant rejection, are also formed in tumours, have a significant beneficial effect on survival and might reflect the generation of an effective immune response in close proximity to the tumour. Thus, the facilitation of TLS formation in tumour stroma could provide novel means to improve the efficiency of immunotherapy and other standard therapies. However, little is known about the mechanisms regulating the formation of tumour-associated TLS. Studies of chronic inflammatory diseases and transplant rejection have demonstrated that TLS formation and/or function requires the presence of B cells. Additionally, the infiltration of B cells into the tumour stroma has been demonstrated to be a significant prognostic factor for improved survival in different human tumours. This suggests that B cells could play a beneficial role in anti-tumour immune response not only in the context of antibody production, antigen presentation and Th1-promoting cytokine production, but also TLS formation. This review focuses on the latest discoveries in tumour-infiltrating B cell functions, their role in TLS formation and relevance in human tumour control, revealing novel opportunities to improve cancer therapies.

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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. .

Accurate stratification of tumors is imperative for adequate cancer management. In addition to staging, morphologic subtyping allows stratification of patients into additional prognostic groups. In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation