Scientists Uncover Underlying Mechanisms of Immune Checkpoint Inhibitors

T cell responses in different tumor models are fundamentally similar.

New findings reveal checkpoint inhibitors target only specific subsets of tumor-infiltrating T cell populations during cancer treatment.

In a study published in Cell, investigators sought to comprehensively profile the effects of checkpoint blockades on tumor immune infiltrates in human melanoma and murine tumor models.

They analyzed infiltrating immune cells from mouse tumor models and human melanomas treated with either anti-CTLA-4 or anti PD-1 checkpoint inhibitors. Thirty-three surface markers and 10 intracellular markers were analyzed using mass cytometry to characterize infiltrating cells.

“The clinical successes of checkpoint blockade have gotten out ahead of our understanding of how these drugs work,” said author Jim Allison, PhD. “In some ways, that’s a good problem to have, but we need greater understanding of the basic science behind these drugs to use them more effectively for patients.”

Findings from the analysis showed treatment with anti-CTLA-4 increased the presence of ICOS-containing CD4 effector T cells, which were strongly associated with smaller tumors in the mice.

Both anti-PD-1 and anti-CTLA-4 treatments expanded the presence of CD8 T cells, which was also associated with smaller tumors in mice.

Lastly, the PD-1 positive CD8 T cells had an exhausted-like phenotype. This means they have markers of inactivity, including the presence of other immune checkpoints, but are not known to be inactive and most likely still have significant functional activity.

“These cells are boosted by anti-PD-1, but they keep their exhausted phenotype, which suggests they’ll shut down when the PD-1 antibody is withdrawn,” Allison said.

The findings highlight the need for these drugs to be administered for long periods, which is currently 1 or 2 years of treatment.

Overall, anti-PD-1 and anti-CTLA-4 treatments expanded the same T cell infiltrates in both tumor types. Although their mechanisms appear to be independent of tumor characteristics, these characteristics are likely to affect the magnitude of responses.

Subsequent analyses of surgically removed human melanoma tumors revealed the anti-PD-1 and anti-CTLA-4 each expanded the T cell populations analogous to those in the mouse models.

The authors noted that although the findings show promise, more research needs to be done in larger studies.