Anti-CTLA4 activates intratumoral NK cells and combination with IL15/IL15Rα complexes enhances tumor control

• Published in: Cancer immunology research 2019-06, Vol.7 (8), p.1371-1380
• Main Authors: Sanseviero, Emilio, O’Brien, Erin M., Karras, Jenna R., Shabaneh, Tamer B., Aksoy, B. Arman, Xu, Wei, Zheng, Cathy, Yin, Xiangfan, Xu, Xiaowei, Karakousis, Giorgos, Amaravadi, Ravi, Nam, Brian T., Turk, Mary Jo, Hammerbacher, Jeffrey E., Schuchter, Lynn, Mitchell, Tara C., Liu, Qin, Stone, Erica L.
• Format: Article
• Language: English
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-18-0386

Antibodies targeting CTLA4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, a majority of patients across tumor types fail to respond. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In murine models anti-CTLA4 efficacy depends on interactions between the Fc region of anti-CTLA4 antibodies and Fc receptors (FcRs). Anti-CTLA4 binding to FcRs has been linked to depletion of intratumoral Tregs. In agreement with previous studies we find that intratumoral Tregs have the highest expression of surface CTLA4 (sCTLA4) and anti-CTLA4 leads to Fc/FcR-dependent depletion of intratumoral Tregs. This Treg depletion coincided with activation and degranulation of intratumoral NK cells. Similarly, in patient-derived tumor tissue Tregs have the highest sCTLA4 expression, and intratumoral Tregs express more sCTLA4 than circulating Tregs. Interestingly, patients who benefit from Ipilimumab have higher intratumoral CD56 expression. Furthermore, in a murine model combination therapy with anti-CTLA4 plus IL15/IL15Rα complexes enhanced tumor control compared to either monotherapy.