LAG3-LaIL2 fusion protein prevents T-cell exhaustion and reinvigorates antitumor immunity in colon cancer.

Robust antitumor immunity in solid tumors is frequently hampered by T-cell exhaustion, a state of T-cell dysfunction driven by chronic antigen exposure within the tumor microenvironment (TME). The inhibitory receptor LAG3 is highly expressed on these exhausted T cells, acting as a critical brake on their function. While interleukin-2 (IL2) is vital for T-cell proliferation and survival, its systemic administration often leads to severe side effects and can activate suppressive regulatory T cells. Furthermore, tumor-infiltrating lymphocytes (TILs) in conditions like colon cancer often exhibit defective IL2 signaling, creating a need for targeted IL2 delivery to restore their function without broad systemic exposure.

Researchers engineered LAG3-LaIL2, a fusion protein designed to selectively deliver low-affinity IL2 to LAG3+CD8+ tumor-infiltrating lymphocytes (TILs). The study utilized a colon cancer model in mice to evaluate the therapeutic potential of LAG3-LaIL2. They assessed its impact on the expansion and exhaustion trajectory of tumor-specific CD8+ T cells, as well as its effects on tumor regression and overall survival. Mechanistic investigations included analyzing IL2R-JAK3-STAT5 signaling and CD122 upregulation in TILs, alongside evaluating systemic antitumor immunity in draining lymph nodes.

LAG3-LaIL2 demonstrated significant therapeutic effects by targeting exhausted T cells. It expanded pre-exhausted tumor-specific CD8+ T cells and reprogrammed their exhaustion trajectory, shifting them toward an intermediate effector state rather than terminal exhaustion. This intervention led to tumor regression and prolonged survival in the treated mice. Mechanistically, LAG3-LaIL2 restored IL2R-JAK3-STAT5 signaling within TILs by upregulating the high-affinity IL2 receptor subunit CD122, thereby restoring their functionality. Furthermore, the fusion protein amplified tumor-specific effector and memory T cells in draining lymph nodes, which enabled systemic antitumor immunity against distal tumors and effectively prevented tumor recurrence. The selective delivery mechanism of LAG3-LaIL2 was crucial for these effects.

LAG3-LaIL2 expanded pre-exhausted tumor-specific CD8+ T cells, reprogrammed their exhaustion trajectory toward an intermediate effector state, and prevented terminal exhaustion, leading to tumor regression and prolonged survival in mice.