Neoantigen driven B cell and CD4⁺T follicular helper cell collaboration promotes robust anti-tumor CD8⁺T cell responses

Abstract

CD4+ T follicular helper (TFH) cells provide help to B cells, which is critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To investigate further, we developed an LUAD model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells were necessary for tumor control, as were effector CD8+ T cells. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens. Thus, tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells.Abstract Figure

The role of B cells in cancer development

“…Germinal center (GC) B cells could be activated by TFH-B interaction and further differentiate into short-term living plasma cells, long-term living plasmablasts, and memory B cells. The singlecell RNA sequencing result of tumor-infiltrating lymphocytes in many studies revealed the presence of GC B cells in the TME (9,16), yet the role of GC B cells is not well known. The study done by Cui et al in lung adenocarcinoma patients elucidated that GC B cells facilitate the function of CD8 + T cells in antitumor immunity via the TFH-GC B cell interaction in a neoantigen-dependent manner (9).…”

“…The singlecell RNA sequencing result of tumor-infiltrating lymphocytes in many studies revealed the presence of GC B cells in the TME (9,16), yet the role of GC B cells is not well known. The study done by Cui et al in lung adenocarcinoma patients elucidated that GC B cells facilitate the function of CD8 + T cells in antitumor immunity via the TFH-GC B cell interaction in a neoantigen-dependent manner (9). They utilized a lung adenocarcinoma cell line (KP) with limited somatic mutations, which means that there are few or no neoantigen expression and weak B/T cell responses so that B cell or T cell depletion doesn't affect the tumor growth.…”

“…The inoculation of KP-HELLO cells in B cell knockout or TFH knockout mice showed much faster tumor growth and weaker CD8 + T cell function compared to tumor growth inoculated in WT mice, suggesting that the GC B cells that recognize the neoantigen and further interact with activated CD4 + T cells are able to support CD8 + T cells function in TME. Further results demonstrated that interaction between neoantigen-specific TFH and GC B cells and interleukin-21 (IL-21) secreted by TFH cells are necessary for the cytotoxicity of CD8 + T cells (9).…”

“…B cell depletion in mice by anti-IgM treatment from birth showed resistance to syngeneic fibrosarcoma and reduced incidence of pulmonary metastasis (8). In contrast, the lung adenocarcinoma cell inoculation in µMT mice failed to show any difference to WT mice ( 9), yet the µMT mice had faster tumor growth than WT mice when the tumor cell line was transfected with B cellspecific neoantigen (9). The function of B cells in tumor growth seems to vary among different tumor cell lines.…”

B cell deficiency promotes the initiation and progression of lung cancer

“…B cell frequency in tumor is positively correlated with patient survival, representing a novel prognostic cellular biomarker (21). Moreover, the presence of B cells in tertiary lymphoid structure (TLS) is positively associated with protective tumor immunity, including high levels of naïve, memory, and activated T cells, and low levels of exhausted T cells and Tregs (22)(23)(24).…”