Adoptively Transferred Immune T Cells Eradicate Established Tumors despite Cancer-Induced Immune Suppression

Abstract

Myeloid-derived CD11b+Gr1+ suppressor cells (MDSC) and tumor-associated macrophages (TAM) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that immune T cells adoptively transferred eradicate well-established tumors in the presence of MDSC and TAM which are strongly immunosuppressive ex vivo. These MDSC and TAM were comparable in levels and immunosuppression among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer tumor vasculature and cancer cells disappeared simultaneously. During T-cell mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAM) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor-burden supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses.

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation

“…YFP×1D9×Rag −/− double-transgenic mice were generated as a pure source of fluorescently labeled 1D9tg T cells. YFP-transgenic Rag −/− mice have been described (29). OTIxRag −/− mice (B6.129S7- Rag1 tm1Mom Tg(TcraTcrb)1100Mjb) were obtained by breeding Rag −/− and TCR OT-I-transgenic mice (provided by Matthew Mescher, University of Minnesota, Minneapolis, MN).…”

“…Implantation of windows, cancer cell injection, confocal microscopy and data analysis were done as described (29,32). Detailed information are provided in Supplementary Methods.…”

The New Era of Cancer Immunotherapy

“…Many tumors are highly infiltrated with suppressive cells such as regulatory T cells (Tregs), MDSCs, and so-called M2 suppressive macrophages. In addition, tumors cells and the associated stroma can express inhibitory molecules such as PD-L1, FAS, or TGF-β that can kill or inhibit transferred cells (Arina et al, 2014). One advantage of adoptive transfer protocols is that T cells can be manipulated ex vivo and strategies to overcome tumor-induced immune suppression can be directly engineered into them.…”

Adoptive immunotherapy via CD4+ versus CD8+ T cells

“…Other barriers to the success of ACT include tumor stroma associated immunosuppression (Phan and Disis, 2008). Cellular components in tumor stroma, including cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSC), and tumorassociated macrophages (TAMs) inhibit T cell function (Arina and Bronte, 2015;Arina et al, 2014;PhanLai et al, 2013). However, reports have shown the…”