1. LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade
- Author
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Hickman, Amber, Koetsier, Joost, Kurtanich, Trevin, Nielsen, Michael C., Winn, Glenn, Wang, Yunfei, Bentebibel, Salah-Eddine, Shi, Leilei, Williams, Simone PunLeila, Haymaker, Cara, Chesson, Charles B., Faak, Faisal, Dominguez, Ana L., Jones, Richard, Kuiatse, Isere, Caivano, Amy R., Khounlo, Sayadeth, Warier, Navin D., Marathi, Upendra, Biediger, Robert V. MarkeRonald J., Craft, John W., Jr., Hwu, Patrick, Davies, Michael A., Woodside, Darren G., Vanderslice, Peter, Diab, Adi, Overwijk, Willem W., and Hailemichael, Yared
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Drug therapy ,Physiological aspects ,Models ,Methods ,Health aspects ,Cancer treatment -- Methods -- Physiological aspects ,Immunologic factors -- Physiological aspects -- Health aspects ,Immunotherapy -- Physiological aspects ,Integrins -- Physiological aspects -- Health aspects ,Melanoma -- Models -- Physiological aspects -- Drug therapy ,Immunity -- Physiological aspects -- Health aspects ,Cancer -- Care and treatment - Abstract
Introduction Immune checkpoint blockade (ICB) Abs that target programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which are focused on activating and mobilizing the body's immune system [...], The inability of [CD8.sup.+] effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) increased [CD8.sup.+] Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral [CD8.sup.+] Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti-CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cellexclusionary TME to a T cell-enriched TME through mechanisms involving cooperation with innate immune cells.
- Published
- 2022
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