Cross-presentation of tumour antigens by human induced pluripotent stem cell-derived CD141+XCR1+ dendritic cells

Abstract

Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8 þ T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A*0201 þ iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8a þ DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8 þ T-cell clone and stimulate primary Melan A-specific responses among naïve T cells from an HLA-A*0201 þ donor. Given that CD141 þ XCR1 þ DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumourspecific immune responses.

Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells

“…S1A). The pMCs were treated with GM-CSF and IL4 (days [23][24]. After 3 days of culture, the pMCs differentiated into DC-like cells (pMC-DC; days [26][27].…”

“…Previous studies have established methods of generating DCs from PSCs, and demonstrated the utility of PSC-derived DCs in cancer immunotherapy (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). However, generating a large number of DCs from ESCs or iPSCs has required a scaling-up of the initial volume of undifferentiated PSCs.…”

Induced pluripotent stem cells in hematology: current and future applications

“…The ability to generate a potentially unlimited source of DCs from iPS cells offers the possibility of harnessing their capacity for cross-priming cytotoxic T lymphocytes inducing a tumor-specific immune response. 66 …”

Current challenges in the therapeutic use of induced pluripotent stem cells (iPSCs) in cancer therapy

“…Despite the promising results, isolation and in vitro propagation of DCs still represents the most challenging task which also increases the overall costs. This therapeutic limitation of DCs can be overcome by using iPSCs-derived DCs and hence represents the renewable source to broaden the immunotherapeutic applications [46]. Silk et al have successfully generated CD141 + XCR1 + DCs from iPSCs using combination of stem cell factor (SCF), granulocyte macrophage-colony stimulating factor (GM-CSF), bone morphogenetic protein-4 (BMP4) and vascular endothelial growth factor (VEGF) without the usage of animal products.…”