LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade
Amber Hickman, … , Willem W. Overwijk, Yared Hailemichael
Amber Hickman, … , Willem W. Overwijk, Yared Hailemichael
Published May 12, 2022
Citation Information: J Clin Invest. 2022;132(13):e154152. https://doi.org/10.1172/JCI154152.
View: Text | PDF
Research Article

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

Abstract

The inability of CD8+ 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+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ 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 cell–exclusionary TME to a T cell–enriched TME through mechanisms involving cooperation with innate immune cells.

Authors

Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C. Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, 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 Jr., Patrick Hwu, Michael A. Davies, Darren G. Woodside, Peter Vanderslice, Adi Diab, Willem W. Overwijk, Yared Hailemichael

×

Figure 7

CD8+ Teff i.t. sequestration is dependent on neutrophils in 7HP349-treated mice.

Options: View larger image (or click on image) Download as PowerPoint
CD8+ Teff i.t. sequestration is dependent on neutrophils in 7HP349-treat...
(A) Mice treated as in Figure 6A. CD11a expression on CD8+ and CD4+ Teff after IgG or anti-Ly6G treatment (n = 6). (B) CD49d expression on CD8+ and CD4+ Teffs after IgG or anti-Ly6G treatment (n = 6). Data in A and B are represented as mean ± SEM. *P < 0.05, unpaired t test. (C and D) Mice bearing 4-day s.c. B16 tumors received 6-day–cultured V-effLuc–transduced pmel-1 T cells i.v. after vaccination with gp100/saline and anti–CTLA-4 i.p. and/or 7HP349, vehicle, IgG, or anti-Ly6G, as indicated. (C) Treatment schematic. (D) V-effLuc–transduced pmel-1 T cells are visualized by whole mouse imaging 4 days (top panel) and 7 days (bottom panel) after vaccination. Combination of bar and dot plots showing absolute pmel-1 T cell luminescence (photons s–1). Data are represented as mean ± SEM. n = 5. Analyses were performed using 1-way ANOVA, Tukey’s test. *P < 0.05; **P < 0.01.