Abstract
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3− NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3− cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.
Highlights
Several reports have shown that mesenchymal stromal cells (MSC) can exert potent immunosuppressive effects leading to the downregulation of T and natural killer (NK) cell responses; the interaction between Mesenchymal stromal cells (MSC) isolated from bone marrow and effector lymphocytes can lead to the suppression of T cell proliferation and NK cell cytotoxic activity [1,2,3,4,5,6,7]
tumor-associated fibroblasts (TAF) and FB reacted with the NKG2D and DNAM1 receptors when used as chimeric molecules and with antibodies to the NKG2D ligands (NKG2D-L) (MICA and ULBP3) and the DNAM1 ligands (DNAM1-L) (PVR) (Figures S1B,D in Supplementary Material)
We analyzed whether co-culture of NK cells with CRC-derived MSC could affect the killing of established CRC cell lines
Summary
Several reports have shown that mesenchymal stromal cells (MSC) can exert potent immunosuppressive effects leading to the downregulation of T and natural killer (NK) cell responses; the interaction between MSC isolated from bone marrow and effector lymphocytes can lead to the suppression of T cell proliferation and NK cell cytotoxic activity [1,2,3,4,5,6,7]. The use of tumor cells expressing fibroblast activation protein as a vaccine resulted in the elimination of solid tumor and impairment of vascular dissemination This effect was accompanied by tumor infiltration of CD8+ T cells, reduction of TAF number and inhibition of the recruitment of immunosuppressive cells within the tumor [16,17,18,19]. TAF from head and neck cancer can inhibit T cell proliferation, further suggesting that mesenchymal cells can regulate the antitumor immune response [21] These findings indicate that in humans MSC can be a suitable target for cancer therapies aimed to revert their immunosuppressive effect and allow the development of NK cell-mediated antitumor response [9]. The presence of functional NK cells can contribute both to CRC cell control and to the success of immunotherapy
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