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.
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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

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Figure 10

CXCL12 gene expression signatures predict response to CTLA-4 checkpoint blockade in melanoma.

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CXCL12 gene expression signatures predict response to CTLA-4 checkpoint ...
Human cancer patients (n = 14) are stratified based upon best overall response (BOR), as indicated in each graph. Individual gene expression changes between baseline and on-treatment 8 weeks after treatment with ipilimumab and tilsotolimod (TLR9 agonist). Box plots show individual gene normalized expression at baseline and week 8 in the local injected lesions. (A) CXCL12; (B) CXCR4; (C) S100A12; (D) CD1C; (E) CD8A; (F) CD8B. P values indicate significance using parametric t test (left panels) and nonparametric test (right panels). Data are presented as median, and whiskers on the box plots extend minimum to maximum points. The top and bottom lines of the box plots represent the interquartile range (IQR), the midline represents the median, and the whiskers on the box plots represent minimum and maximum values. Data analyses were performed for responders (Res) and nonresponders (nRes). Baseline versus on-treatment, paired t test; baseline alone, unpaired t test.