PD-1/CTLA-4 Blockade Leads to Expansion of CD8(+)PD-1(int) TILs and Results in Tumor Remission in Experimental Liver Cancer

BACKGROUND: Checkpoint inhibitors act on exhausted CD8⁺ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. METHODS: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8⁺ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells. RESULTS: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8⁺ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8⁺ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8⁺ TILs, while terminally exhausted CD8⁺ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8⁺ TILs. Unexpectedly, progenitor-exhausted CD8⁺ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile. CONCLUSION: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8⁺ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8⁺ T cells while preventing their development into terminally exhausted CD8⁺ TILs in the TME. This finding could have important implications for future T-cell therapies.