Research Article: B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses

Date Published: July 5, 2018

Publisher: Public Library of Science

Author(s): Renata Ariza Marques Rossetti, Noely Paula Cristina Lorenzi, Kaori Yokochi, Maria Beatriz Sartor de Faria Rosa, Luciana Benevides, Paulo Francisco Ramos Margarido, Edmund Chada Baracat, Jesus Paula Carvalho, Luisa Lina Villa, Ana Paula Lepique, Takuma Kato.


Immune evasion by tumors includes several different mechanisms, including the inefficiency of antigen presenting cells (APCs) to trigger anti-tumor T cell responses. B lymphocytes may display a pro-tumoral role but can also be modulated to function as antigen presenting cells to T lymphocytes, capable of triggering anti-cancer immune responses. While dendritic cells, DCs, are the best APC population to activate naive T cells, DCs or their precursors, monocytes, are frequently modulated by tumors, displaying a tolerogenic phenotype in cancer patients. In patients with cervical cancer, we observed that monocyte derived DCs are tolerogenic, inhibiting allogeneic T cell activation compared to the same population obtained from patients with precursor lesions or cervicitis. In this work, we show that B lymphocytes from cervical cancer patients respond to treatment with sCD40L and IL-4 by increasing the CD80+CD86+ population, therefore potentially increasing their ability to activate T cells. To test if B lymphocytes could actually trigger anti-tumor T cell responses, we designed an experimental model where we harvested T and B lymphocytes, or dendritic cells, from tumor bearing donors, and after APC stimulation, transplanted them, together with T cells into RAG1-/- recipients, previously injected with tumor cells. We were able to show that anti-CD40 activated B lymphocytes could trigger secondary T cell responses, dependent on MHC-II expression. Moreover, we showed that dendritic cells were resistant to the anti-CD40 treatment and unable to stimulate anti-tumor responses. In summary, our results suggest that B lymphocytes may be used as a tool for immunotherapy against cancer.

Partial Text

Human Papillomavirus is the main etiologic factor for cervical cancer and a percentage of other anogenital and oropharyngeal cancers [1,2]. The natural history of cervical cancer is long, involving molecular and cellular alterations, as well as immune evasion [3,4]. Both effector and regulatory T lymphocytes infiltrate cervical tumors, where low effector/regulatory T cell ratio is a poor prognostic factor for disease progression and metastasis [5]. Systemically, it has been observed that circulating T cells from cervical cancer patients preferentially exhibit regulatory phenotype, with low proliferation and IL-10 secretion upon stimulation with HPV antigens, indicating that these tumors are capable of inducing tolerance [6].

Many years ago, Doan and collaborators demonstrated, in a transgenic experimental model, that there was peripheral tolerance toward HPV antigens [37]. Later, van der Burg and collaborators also showed evidence of peripheral tolerance in cervical cancer patients [6]. Several research groups have been investigating the mechanisms underlying the tolerance toward HPV antigens, including ours [25,29]. In this manuscript, we have shown, that simply removing T lymphocytes from the tumor bearing host and transferring them to another host, with established but undetectable tumors to the naked eye and touch, allowed these cells to display anti-tumor activity. This result indicated, first, that T cells from tumor bearing mice had the potential to recognize and respond to tumor antigens; second, that the tumor induced a tolerogenic environment in the lymph nodes and spleen, therefore causing systemic effects on the immune system.




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