Contrasting effects of cyclophosphamide on anti-CTLA-4 blockade therapy in two mouse tumor models

Summary

Immune checkpoint blockade is a promising anti-cancer therapy, but must be used in combination with other anti-cancer therapies to increase therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that exhibits immune-modulating effects. In this study, we examined the effect of CP on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after intraperitoneal (i.p.) injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8⁺ T cells. In the RENCA renal carcinoma model, the anti-tumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin (IL)-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10) were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1⁺ cells augmented the anti-tumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. CP augments the anti-tumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect via induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of IL-6.

This article is protected by copyright. All rights reserved.

http://ift.tt/2umrTdO