Abstract
PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti–PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti–PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti–PD-1–induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti–PD-1 (PD-1–laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1–laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1–laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1–laIL-2. Collectively, these results highlight that PD-1–laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.
Highlights
Increased levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with cancer [1–3]
To reduce the binding of IL-2 to Treg cells that express IL-2Rα and IL-2Rβ and potentially absorb more IL-2, we selected a low-affinity IL-2 (IL-2 R38L F42A, lowaffinity IL-2 (laIL-2)) that has greatly reduced binding to both IL-2Rα and IL-2Rβ for Treg cells
As T cells are important for PD-1–laIL-2 treatment and PD-1– laIL-2 does not bind to peripheral T cells, we proposed that PD-1– laIL-2 can preferentially expand TILs but not T cells in lymphoid tissues
Summary
Increased levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with cancer [1–3]. Anti– PD-1/PD-L1–based cancer immunotherapies have revolutionized the treatment of cancers [4–8], and TIL abundance can be used as a prediction marker for immunotherapy responsiveness [9, 10]. Even though PD-1/PD-L1 blockade can release the brake on the T cell response, T cells are not fully functional and are limitedly expanded in the tumor [11, 12]. Most patients either fail to respond or develop adaptive resistance after an initial response [13–15]. The role of T cell–associated cytokines in the tumor microenvironment for anti–PD-1/PD-L1 responsiveness has not been fully studied. It is possible that additional T cell–driven cytokine therapy might overcome PD-1 therapy resistance
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