Patients with microsatellite-stable (MSS) colorectal cancer have limited clinical benefit with PD-1 blockade [1, 2]. These tumors are poorly immunogenic and highly infiltrated by immunosuppressive populations . In this context, identification of drug combinations both inducing immunogenicity and modulating tolerogenicity is crucial for the sensitization of MSS colorectal cancer to immune-checkpoint inhibitors. The aim of this study was to evaluate the immunological properties of the trifluridine/tipiracil and oxaliplatin combination in the murine MSS colorectal cancer CT26 model.
Immunogenic cell death was evaluated both in vitro and in vivo (HMGB1/ATP release, calreticulin and EIF2α endoplasmic reticulum stress marker). Both antitumor CD8 (IFNγ, Granzyme B, PD-1) and tolerogenic (including Treg, polymorphonuclear-granulocytic/monocytic myeloid-derived suppressor cells and tumor-associated macrophages [TAM]) responses were analyzed by immunochemistry and flow cytometry.
Combined therapy induced all immunogenic cell death markers in vitro. In tumor tissue, HMGB1 nuclear delocalization and EIF2α phosphorylation were significantly increased after trifluridine/tipiracil and oxaliplatin exposure as compared to each single agent; no effect was seen with the single agents. These immunogenic signals allow the recruitment of PD-1+ CD8 cells with high capacity for production of IFNγ, TNFα and granzyme B production capacities. Furthermore, the trifluridine/tipiracil and oxaliplatin combination was seen to markedly deplete TAM, in particular TAM2.
The trifluridine/tipiracil and oxaliplatin combination induces immunogenic cell death and antitumor CD8 activation as well as depletion of immunosuppressive TAM2 in MSS colorectal cancer. This chemotherapy combination could therefore be considered as a potential new therapeutic option for immune checkpoint inhibitor sensitization in MSS colorectal cancer. 1. Le DT, Uram JN, Wang H, et al. N Engl J Med. 2015;372(26):2509-20. 2. Lochhead P, Kuchiba A, Imamura Y, et al. J Natl Cancer Inst. 2013;105(15):1151-6. 3. De Smedt L, Lemahieu J, Palmans S, et al. Br J Cancer. 2015;113(3):500-9.
Clinical trial identification
Legal entity responsible for the study
Servier and CGFL.
F. Ghiringhelli: Consultant: AstraZeneca, Servier, Roche, BMS, Enterome, Sanofi. V. Cattan, E. Peranzoni, N. Amellal: Employee of Servier. All other authors have declared no conflicts of interest.