CXCR3 on transferred T cells enables vaccine-boosted adoptive T-cell therapy in solid tumors

Adoptive T-cell therapy (ACT) has shown promising results in treating hematological malignancies, but its effectiveness against solid tumors remains limited. Cancer vaccines have been employed to enhance ACT, yet the underlying mechanisms of this combination have remained unclear. In this study, researchers investigated the synergistic effects of ACT combined with modified viral vector vaccines, specifically chimpanzee adenovirus ChAdOx1 and modified vaccinia Ankara (MVA), encoding tumor antigens.

The researchers discovered that blocking the PD1 pathway did not improve ACT efficacy. However, when combined with ChAd/MVA vaccination, there was a significant increase in the regression of established tumors. This combination therapy was correlated with the expansion of tumor-reactive T cells within lymphoid organs and a higher infiltration of T cells into the tumors.

To understand the mechanisms behind this synergistic effect, the researchers focused on the role of CXCR3, a chemokine receptor expressed on the transferred T cells but not on host cells.

The study revealed that ChAd priming induced the expression of CXCL10 and CXCL9, two CXCR3 ligands, in the vaccine-draining lymph node. This induction of CXCR3 ligands facilitated the recruitment of transferred T cells to the lymph node, independent of any direct interaction with cognate antigens. Crucially, the expression of CXCR3 on the transferred T cells, rather than on the host cells, was essential for the anti-tumor effect of the combination therapy.

This finding suggests that CXCR3 on the transferred T cells acts as a determining factor in the synergy between ACT and vaccination.

The implications of these findings extend beyond ACT and vaccination combinations. They also provide a rationale for integrating viral-vector vaccines with TCR-T therapies. Furthermore, the researchers emphasize the importance of selecting or engineering T cells that retain CXCR3 expression to maximize the therapeutic potential of this approach.