Immunologic synergy between intermittent NSAID administration and antigen specific vaccination in inhibiting the development of intestinal polyps in the APC(Min/+)

Abstract

Abstract Introduction Studies from our group have shown that administration of NSAIDs in mouse models of Familial Adenomatous Polyposis results in a decrease in polyp formation and a significant increase in CD8 tumor infiltrating lymphocytes with downregulation of PD-L1 expression in tumors. We questioned whether a short course of NSAID could be used in combination with vaccination to even further reduce the development of intestinal polyps. Methods At 4–6 weeks of age, APC(Min/+) male/female mice were given CFA/IFA adjuvant with or without a multi-antigen (EGFR, COX2, CDC25B) peptide vaccine. Upon start of vaccinations, normal food or 400ppm naproxen mixed with food was provided either continuously (CON; 18w on) or intermittently (INT; 3w on + 3w off for 3 cycles). Animals were euthanized at 22±1 weeks and tumors quantified. Systemic and tissue specific immunity was measured by ELISPOT, FACS, and direct tumor staining. Results Tumor development was significantly inhibited both by vaccine alone and naproxen alone (p<0.0001). Combining naproxen (INT or CON) with vaccine was additive compared to vaccine alone (p<0.0001) and naproxen alone (INT+Vaccine p<0.0007; CON+Vaccine p<0.0003). INT naproxen was as effective as CON, with or without vaccine (p>0.999). Mice with greater tumor inhibition demonstrated higher magnitude antigen specific T-cell responses (p=0.0441, r=−0.423) and CD8+ T-cell infiltration (p<0.0001, r=−0.506) than those with less protection. Conclusions Data demonstrates that short-term administration of NSAIDs may be as effective as the more toxic long-duration alternative. Further, a short course of NSAID significantly synergizes with antigen specific vaccination to inhibit the development of polyps.