LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade

• DOI: 10.1172/jci154152
• Publication Date: 2022-05-12T16:00:27Z
• Authors: Amber Hickman; Joost Koetsier; Trevin Kurtanich; Michael C. Nielsen; Glenn Winn; Yunfei Wang; Salah-Eddine Bent...; Leilei Shi; Simone Punt; Leila Williams; Cara Haymaker; Charles B. Chesson; Faisal Fa’ak; Ana L. Dominguez; Richard Jones; Isere Kuiatse; Amy R. Caivano; Sayadeth Khounlo; Navin D. Warier; Upendra Marathi; Robert V. Market; Ronald J. Biediger; John W. Craft; Patrick Hwu; Michael A. Davies; Darren G. Woodside; Peter Vanderslice; Adi Diab; Willem W. Overwijk; Yared Hailemichael
• Keywords: Cancer Immunotherapy

The inability of CD8+ effector T cells (Teffs) to reach tumor is an important aspect resistance cancer immunotherapy. recruitment these the microenvironment (TME) regulated by integrins, a family adhesion molecules that are expressed on cells. Here, we show 7HP349, small-molecule activator lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated preferential localization tumor-specific improved antitumor response. 7HP349 monotherapy had modest effects anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic lymphocyte-associated protein 4 (anti-CTLA-4) increased Teff intratumoral sequestration synergized in cooperation neutrophils inducing regression. enrichment activity depended CXCL12. We analyzed gene expression profiles using RNA from baseline samples 14 melanoma patients. identified CXCL12 as possibly improving likelihood or response anti-CTLA-4 therapies. Our results provide proof-of-principle demonstration LFA-1 could convert cell-exclusionary TME cell-enriched through mechanisms involving innate immune