Fc effector function contributes to the activity of human anti-CTLA-4 antibodies

Arce Vargas, F. et al. (2018) Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell, 33(4), 649-663.e4. (doi: 10.1016/j.ccell.2018.02.010) (PMID:29576375) (PMCID:PMC5904288)

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Publisher's URL: http://dx.doi.org/10.1016/j.ccell.2018.02.010


With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Item Type:Articles
Additional Information:Professor John Le Quesne is a member of The TRACERx Lung Consortium (TRAcking Cancer Evolution through Therapy (Rx)).
Glasgow Author(s) Enlighten ID:Le Quesne, Professor John
Authors: Arce Vargas, F., Furness, A. J.S., Litchfield, K., Joshi, K., Rosenthal, R., Ghorani, E., Solomon, I., Lesko, M. H., Ruef, N., Roddie, C., Henry, J. Y., Spain, L., Ben Aissa, A., Georgiou, A., Wong, Y. N. S., Smith, M., Strauss, D., Hayes, A., Nicol, D., O'Brien, T., Mårtensson, L., Ljungars, A., Teige, I., Frendéus, B., Pule, M., Marafioti, T., Gore, M., Larkin, J., Turajlic, S., Swanton, C., Peggs, K. S., Quezada, S. A., Harrington, K., Melcher, A., Wotherspoon, A., Francis, N., Challacombe, B., Fernando, A., Hazell, S., Chandra, A., Pickering, L., Lynch, J., Rudman, S., Chowdhury, S., Harrison-Phipps, K., Varia, M., Horsfield, C., Polson, A., Stamp, G., O'Donnell, M., Drake, W., Hill, P., Hrouda, D., Mayer, E., Olsburgh, J., Kooiman, G., O'Connor, K., Stewart, G., Aitchison, M., Tran, M., Fotiadis, N., Verma, H., Lopez, J., Lester, J., Morgan, F., Kornaszewska, M., Attanoos, R., Adams, H., Davies, H., Fennell, D., Shaw, J., Le Quesne, J., Nakas, A., Rathinam, S., Monteiro, W., Marshall, H., Nelson, L., Bennett, J., Riley, J., Primrose, L., Martinson, L., Anand, G., Khan, S., Nicolson, M., Kerr, K., Palmer, S., Remmen, H., Miller, J., Buchan, K., Chetty, M., Gomersall, L., Lock, S., Naidu, B., Langman, G., Trotter, S., Bellamy, M., Bancroft, H., Kerr, A., Kadiri, S., Webb, J., Middleton, G., Djearaman, M., Summers, Y., Califano, R., Taylor, P., Shah, R., Krysiak, P., Rammohan, K., Fontaine, E., Booton, R., Evison, M., Crosbie, P., Moss, S., Idries, F., Novasio, J., Joseph, L., Bishop, P., Chaturvedi, A., Marie Quinn, A., Doran, H., leek, A., Harrison, P., Moore, K., Waddington, R., Blackhall, F., Rogan, J., Smith, E., Dive, C., Brady, G., Rothwell, D., Gulati, S., Chemie, F., Tugwood, J., Pierce, J., Lawrence, D., Hayward, M., Panagiotopoulos, N., George, R., Patrini, D., Falzon, M., Borg, E., Khiroya, R., Jamal-Hanjani, M., Wilson, G., Juul Birkbak, N., Watkins, T., McGranahan, N., Abbosh, C., Horswell, S., Mitter, R., Escudero, M., Stewart, A., Rowan, A., Hiley, C., Goldman, J., Ahmed, A., Taylor, M., Choudhary, J., Shaw, P., Veeriah, R., Czyzewska-Khan, J., Johnson, D., Laycock, J., Hynds, R., Werner Sunderland, M., Reading, J., Novelli, M., Oukrif, D., Janes, S., Forster, M., Ahmad, T., Ming Lee, S., van Loo, P., Herrero, J., Hartley, J., Kevin Stone, R., Denner, T., Costa, M., Begum, S., Phillimore, B., Chambers, T., Nye, E., Ward, S., Elgar, G., Al-Bakir, M., Carnell, D., Mendes, R., George, J., Navani, N., Papadatos-Pastos, D., Scarci, M., Gorman, P., Lowe, H., Ensell, L., Moore, D., MacKenzie, M., Wilcox, M., Bell, H., Hackshaw, A., Ngai, Y., Smith, S., Gower, N., Ottensmeier, C., Chee, S., Johnson, B., Alzetani, A., Shaw, E., Lim, E., De Sousa, P., Tavares Barbosa, M., Nicholson, A., Bowman, A., Jordan, S., Rice, A., Raubenheimer, H., Proli, C., Elena Cufari, M., Carlo Ronquillo, J., Kwayie, A., Bhayani, H., Hamilton, M., Bakar, Y., Mensah, N., Ambrose, L., Devaraj, A., Buderi, S., Finch, J., Azcarate, L., Chavan, H., Green, S., Mashinga, H., Lau, K., Sheaff, M., Schmid, P., Conibear, J., Ezhil, V., Prakash, V., Danson, S., Bury, J., Edwards, J., Hill, J., Matthews, S., Kitsanta, Y., Suvarna, K., Shackcloth, M., Gosney, J., Postmus, P., Feeney, S., Asante-Siaw, J., Russell, P., Light, T., Horey, T., Blyth, K., Dick, C., and Kirk, A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Cell
Publisher:Elsevier (Cell Press)
ISSN (Online):1878-3686
Published Online:22 March 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cancer Cell 33(4): 649-663.e4
Publisher Policy:Reproduced under a Creative Commons License

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