Purity of transferred CD8+ T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP‐1

• Published in: Immunology and cell biology Vol. 94; no. 8; pp. 802 - 808
• Main Authors: Watson, H Angharad, Dolton, Garry, Ohme, Julia, Ladell, Kristin, Vigar, Miriam, Wehenkel, Sophie, Hindley, James, Mohammed, Rebar N, Miners, Kelly, Luckwell, Rhys A, Price, David A, Matthews, R James, Ager, Ann
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2016; Blackwell Science Ltd
• Subjects: Adoptive Transfer; Animals; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Flow Cytometry; Immunotherapy, Adoptive; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice, Inbred C57BL; Neoplasm Metastasis; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Receptors, Interleukin-1 Type I - deficiency; Receptors, Interleukin-1 Type I - metabolism; Short Communication
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2016.45

Adoptive transfer of tumor‐specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2‐domain‐containing phosphatase 1 (SHP‐1, Ptpn6). Naturally occurring motheaten mice lack SHP‐1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP‐1null mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP‐1 augments the ability of adoptively transferred CD8+ T cells to control tumor growth. This therapeutic effect was only observed in situations where T‐cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non‐CD8+ SHP‐1null hematopoietic cells resulted in lethal motheaten‐like pathology, indicating that systemic inhibition of SHP‐1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP‐1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic.