Abstract: The compositions and methods described herein are useful for diminishing CTL exhaustion in a subject in need thereof, during an immune response to a viral infection or during an immune response to cancer, thereby leading to a greater CTL response against the viral infection or cancer. The invention relates to compositions and methods for the therapeutic intervention of signaling through EP2 and EP4, by inhibiting at least one of EP2, EP4, PGE2, or combinations thereof. The invention also relates to compositions and methods for the therapeutic intervention of signaling through EP2 and EP4, in combination with the therapeutic intervention of signaling through PD-1, by inhibiting at least one of EP2, EP4, PGE2, or combinations thereof, in combination with inhibiting at least one of PD-1, PD-L1, PD-L2, and combinations thereof.