August 2018 - Carmen Stecher

Carmen Stecher, MSc

MedUni Wien RESEARCHER OF THE MONTH, August 2018

PD-1 blockade promotes emerging Immune Checkpoints in enhancing T cell responses to allogeneic DC

Immune checkpoint inhibitors successfully target coinhibitory T cell molecules to promote anticancer immune responses. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in combination with a PD-1 antibody. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients.

Selected Literature

1. Stecher, C., Battin, C., Leitner, J., Zettl, M., Grabmeier-Pfistershammer, K., Holler, C., Zlabinger, G. J., and Steinberger, P. (2017) PD-1 Blockade Promotes Emerging Checkpoint Inhibitors in Enhancing T Cell Responses to Allogeneic Dendritic Cells. Frontiers in immunology 8, 572 doi:10.3389/fimmu.2017.00572 (IF 6,429)
2. Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., Akerley, W., van den Eertwegh, A. J., Lutzky, J., Lorigan, P., Vaubel, J. M., Linette, G. P., Hogg, D., Ottensmeier, C. H., Lebbe, C., Peschel, C., Quirt, I., Clark, J. I., Wolchok, J. D., Weber, J. S., Tian, J., Yellin, M. J., Nichol, G. M., Hoos, A., and Urba, W. J. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363, 711-723 (IF 59,558)
3. Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., Leming, P. D., Spigel, D. R., Antonia, S. J., Horn, L., Drake, C. G., Pardoll, D. M., Chen, L., Sharfman, W. H., Anders, R. A., Taube, J. M., McMiller, T. L., Xu, H., Korman, A. J., Jure-Kunkel, M., Agrawal, S., McDonald, D., Kollia, G. D., Gupta, A., Wigginton, J. M., and Sznol, M. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366, 2443-2454 (IF 59,558)
4. Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R. A., Reed, K., Burke, M. M., Caldwell, A., Kronenberg, S. A., Agunwamba, B. U., Zhang, X., Lowy, I., Inzunza, H. D., Feely, W., Horak, C. E., Hong, Q., Korman, A. J., Wigginton, J. M., Gupta, A., and Sznol, M. (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369, 122-133 (IF 59,558)
5. Nghiem, P. T., Bhatia, S., Lipson, E. J., Kudchadkar, R. R., Miller, N. J., Annamalai, L., Berry, S., Chartash, E. K., Daud, A., Fling, S. P., Friedlander, P. A., Kluger, H. M., Kohrt, H. E., Lundgren, L., Margolin, K., Mitchell, A., Olencki, T., Pardoll, D. M., Reddy, S. A., Shantha, E. M., Sharfman, W. H., Sharon, E., Shemanski, L. R., Shinohara, M. M., Sunshine, J. C., Taube, J. M., Thompson, J. A., Townson, S. M., Yearley, J. H., Topalian, S. L., and Cheever, M. A. (2016) PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 374, 2542-2552 (IF 59,558)