B cell responses and antibody-based therapeutic perspectives in human cancers

Abstract

Background: Immuno-oncology has been focused on T cell-centric approaches until the field recently started appreciating the importance of tumor-reactive antibody production by tumor-infiltrating plasma B cells, and the necessity of developing novel therapeutic antibodies for the treatment of different cancers.

Recent findings: B lymphocytes often infiltrate solid tumors and the extent of B cell infiltration normally correlates with stronger T cell responses while generating humoral responses against malignant progression by producing tumor antigens-reactive antibodies that bind and coat the tumor cells and promote cytotoxic effector mechanisms, reiterating the fact that the adaptive immune system works by coordinated humoral and cellular immune responses. Isotypes, magnitude, and the effector functions of antibodies produced by the B cells within the tumor environment differ among cancer types. Interestingly, apart from binding with specific tumor antigens, antibodies produced by tumor-infiltrating B cells could bind to some non-specific receptors, peculiarly expressed by cancer cells. Antibody-based immunotherapies have revolutionized the modalities of cancer treatment across the world but are still limited against hematological malignancies and a few types of solid tumor cancers with a restricted number of targets, which necessitates the expansion of the field to have newer effective targeted antibody therapeutics.

Conclusion: Here, we discuss about recent understanding of the protective spontaneous antitumor humoral responses in human cancers, with an emphasis on the advancement and future perspectives of antibody-based immunotherapies in cancer.

Keywords: antibody‐based immunotherapies; immunoglobulin class‐switching; tumor microenvironment; tumor‐infiltrating B lymphocytes.

FIGURE 1

Tumor microenvironment and B lymphocytes. (A) CXCL13, secreted in the tumor microenvironment, attracts CXCR5⁺ B cells, CXCR5⁺ TFH cells, and CXCR5⁺ Vγ9Vδ2 γδ T cells that together promote formation of tertiary lymphoid structures. (B) NK cells promote B cell activation by engaging with CD40 on B cell surface through CD40L. NK cells and γδ T cells promote B cell class‐switching by secreting IFN‐γ. Tumor‐associated macrophages promote B cell development, proliferation, and survival by secreting B cells‐activating factor (BAFF) and a proliferation‐inducing ligand (APRIL).

FIGURE 2

Intracellular targeting of mutated oncoproteins by dimeric IgA antibodies. Mutation‐specific dimeric IgA antibodies can bind with PIGR expressed on the epithelial cancer cells of major cancer types and get internalized with a fragment of PIGR known as the secretory component. Internalized dimeric IgA antibodies encounter target antigens in the cytoplasm and could haul them outside of the cells through transcytosis whereby the mutated oncodrivers could be expelled into the extracellular space by secretory IgA. Treatment of PIGR⁺ tumor cells sensitizes them for CD8⁺ cytotoxic T cell‐mediated killing.