AUTHOR=Abdala-Saleh Noor , Lugassy Jennie , Shivakumar-Kalvhati Akshatha , Turky Abeer , Abu Ras Sari , Razon Hila , Berger Nir , Bar-On Dana , Bar-On Yotam , Taura Tetsuya , Wilson David , Karin Nathan 

TITLE=PD-1 and CTLA-4 serve as major gatekeepers for effector and cytotoxic T-cell potentiation by limiting a CXCL9/10-CXCR3-IFNγ positive feedback loop

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1452212

DOI=10.3389/fimmu.2024.1452212

ISSN=1664-3224

ABSTRACT=<p>CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy. Results from a panel of <italic>in vivo</italic> and ex vivo 3D tumor models imply that, beyond driving CD8+ T cells into T-cell exhaustion, a major role of PD-1 and CTLA-4 is in limiting the CXCR3-based self-feeding mechanism of T cell potentiation. This may explain why patients that are CXCL9/CXCL10<sup>high</sup> tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10<sup>low</sup>. It also suggests a therapeutic role for CXCL9-Fc or CXCL10-Fc therapy; herein we demonstrate significant anti-tumor activity in multiple murine tumor models with such agents.</p>