3.3.1　Tumor-Specific Antibodies

In both the serum and the tumor microenvironment, antibodies are frequently found that recognize a broad array of tumor-expressed and self-antigens.These include overexpressed or aberrantly expressed self-antigens, unconventionally modified proteins and normal intracellular molecules.In addition, neoantigens and cryptic peptide antigens that can drive a humoral immune response have been identified from immunoscreening of cDNA libraries from tumor tissues.Such antigens may originate from a frameshift or replacement mutation, an alternative start codon or alternative splicing events.Tumor-specific and self-specific antibodies have been detected in serum from patients with cancer in numerous studies.Furthermore, estimates of the levels of serum autoantibodies against tumor-associated and self-antigens have been proposed for early detection of cancer.At later stages of disease, serum antibodies can serve as potent prognostic markers [47].

One well-known tumor-associated antigen, mucin 1 (MUC1), is overexpressed in tumors in an underglycosylated form.Antibodies against MUC1 are detected in serum from patients at early stages of pancreatic, breast, gastric, lung and ovarian cancer and serve as a marker of improved prognosis.High serum levels of IgG antibodies specific for the Thomsen-Friedenreich antigen(Galβ1-3GalNAcα-O-Ser/Thr) were associated with longer survival in patients with breast and gastric cancer 64, 68.In general, antibodies against known tumor antigens are detectable in the serum of approximately 50% of patients with breast cancer [48].(https://www.daowen.com)

There is no universal single origin for tumor-specific antibodies that are detected in the serum.These antibodies may be produced by plasma cells residing in classical niches, such as the bone marrow or spleen.However, there is also evidence that plasma cells may occupy local tissue niches,especially in the context of chronic inflammation, and in particular in the tumor microenvironment.If plasma cells in tumor-associated TLS produce high levels of tumor-specific antibodies in situ,these antibodies can also be detected in serum.On the other hand, there is also evidence of systemic B cell responses to tumor antigens, as tumor-specific B cells, plasmablasts and plasma cells can be found in peripheral blood.Intra-tumoral antibodies were first detected in the 1970s.In 1996, the presence of IgA1 in preparations from primary breast cancers and their metastases was reported.Multiple lines of evidence now leave no doubt that B cells undergo clonal proliferation,selection for high-affinity antibody and isotype switching within tumor-associated TLS and in less organized structures, ultimately converting to effector/memory B cells and antibody-producing plasma cells.These plasma cells may reside locally and produce high titres of tumor-specific antibodies, as has been shown for breast cancer, melanoma and high-grade serous ovarian cancer.

In medullary carcinoma of the breast, tumor-infiltrating B cells were also shown to produce oligoclonal, somatically mutated anti bodies that bind self-antigens such as cell surface-exposed actin with high affinity.Such antibodies can mediate opsonization, complement-mediated lysis of cancer cells and ADCC executed by natural killer (NK) cells or promote antibody-mediated phagocytosis of tumor cells by macrophages and granulocytes.In vitro studies have demonstrated that B cells from patients with melanoma can produce IgG that is capable of eliminating cancer cells by triggering ADCC.Reports showing that infiltration of melanoma and non-small-cell lung carcinoma by plasma cells and high intra-tumoral immunoglobulin expression in melanoma and head and neck squamous cell carcinoma44 correlate with longer survival indicate the important role of intratumorally localized plasma cells.Clonal expansion of tumor-infiltrating B cells is also associated with a more efficient antitumor response, further strengthening the idea that focused humoral response can have important antitumor effects [49, 50].