Serial low doses of sorafenib enhance therapeutic efficacy of adoptive T cell therapy in a murine model by improving tumor microenvironment.

Hui-Yen Chuang,Ya-Fang Chang,Ren-Shyan Liu,Jeng-Jong Hwang,Reiner Albert Veitia

doi:10.1371/journal.pone.0109992

Abstract

Requirements of large numbers of transferred T cells and various immunosuppressive factors and cells in the tumor microenvironment limit the applications of adoptive T cells therapy (ACT) in clinic. Accumulating evidences show that chemotherapeutic drugs could act as immune supportive instead of immunosuppressive agents when proper dosage is used, and combined with immunotherapy often results in better treatment outcomes than monotherapy. Controversial immunomodulation effects of sorafenib, a multi-kinases inhibitor, at high and low doses have been reported in several types of cancer. However, what is the range of the low-dose sorafenib will influence the host immunity and responses of ACT is still ambiguous. Here we used a well-established E.G7/OT-1 murine model to understand the effects of serial low doses of sorafenib on both tumor microenvironment and transferred CD8+ T cells and the underlying mechanisms. Sorafenib lowered the expressions of immunosuppressive factors, and enhanced functions and migrations of transferred CD8+ T cells through inhibition of STAT3 and other immunosuppressive factors. CD8+ T cells were transduced with granzyme B promoter for driving imaging reporters to visualize the activation and distribution of transferred CD8+ T cells prior to adoptive transfer. Better activations of CD8+ T cells and tumor inhibitions were found in the combinational group compared with CD8+ T cells or sorafenib alone groups. Not only immunosuppressive factors but myeloid derived suppressive cells (MDSCs) and regulatory T cells (Tregs) were decreased in sorafenib-treated group, indicating that augmentation of tumor inhibition and function of CD8+ T cells by serial low doses of sorafenib were via reversing the immunosuppressive microenvironment. These results revealed that the tumor inhibitions of sorafenib not only through eradicating tumor cells but modifying tumor microenvironment, which helps outcomes of ACT significantly.

Highlights

Adoptive T cell therapy (ACT) is considered to be a promising therapeutic strategy for cancer treatment
A wellestablished E.G7/OT-1 murine model was utilized to prove that sorafenib, a multi-kinases targeting drug used in HCC and RCC treatments, can reverse the unfavorable tumor microenvironment and enhance therapeutic efficacies of ACT both in vitro and in vivo
The combination of ACT with chemotherapy for cancer treatments is still challenging because of the immunosuppressive effects of most chemotherapeutic drugs. Chemotherapeutic drugs such as paclitaxel (TAX), cisplatin (CIS), and doxorubicin (DOX) have been shown some positive immunological effects which may help outcomes of ACT. These drugs modify the immune microenvironment via several mechanisms, including better immunogenicity induced by tumor apoptosis [25,26], upregulations of tumor-associated antigens and mannose-6-phosphate (M6P) expressions and modulation of Fas/TRAIL-dependent pathway sensitize tumor cells to cytotoxic T lymphocytes (CTLs) [27,28,29], elimination of Tregs [30,31], and disruption of tumor stromal caused larger numbers of tumor-infiltrating CTLs [32]

Summary

Introduction

Adoptive T cell therapy (ACT) is considered to be a promising therapeutic strategy for cancer treatment. Increasing evidences show that immunosuppressive networks in the tumor microenvironment act as substantial barriers to T cell response. Cancer cells hinder T cells responses through several pathways, including impairing antigen presentation, activating negative costimulatory signals (CTLA-4/B7 and PD-1/PD-L1), secreting immunosuppressive factors (i.e. transforming frowth factor-b (TGF-b) and interleukin-10 (IL-10)) to recruit immunosuppressive cells like regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and triggering proapoptotic pathways (indoleamine 2,3-dioxygenase (IDO), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL)) in effector T cells [2,3]. Combination of ACT and chemotherapy was reported as incompatible due to the induction of lymphopenia and immunosuppressive cytokines, and the inhibition of effector T cell function by chemotherapy at first [7]. Later reports show that preconditioning radiotherapy or chemotherapy performed before CD8+ T cell transfer modifies unfavorable tumor microenvironments [8], and improve the effectiveness of T cell therapy through inducing tumor cell deaths, eliminating Tregs, and enhancing tumor cell killing by effector T cells [9,10]

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Results

Conclusion