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 4

7HP349 enhances CD8+ Teff preferential localization to tumor.

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7HP349 enhances CD8+ Teff preferential localization to tumor. (See Suppl...
(See Supplemental Figures 10–12). (A) Mice were treated as in Figure 3A. LFA-1 expression on CD8+ or CD4+ Teffs from tumor and spleen tissues (n = 5). Data are represented as mean ± SEM, 1-way ANOVA, Tukey’s test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (B) Vitiligo expression in mice (left) and the percentage of mice with vitiligo (right). (C and D) C57BL/6 mice bearing 3-day-old s.c. B16.BL6 tumors received i.p. 7HP349 or vehicle or i.d. GVAX with i.p. anti–CTLA-4, as described in Figure 1E, and mAb depletion of CD8+ T cells or NK cells on days 3, 5, 7, 9, and 11 after tumor injection (n = 10). (C) Tumor growth curves of biologically independent mice by treatment group. (D) Average tumor burden (mean ± SEM) for mice treated with anti–CTLA-4_GX plus vehicle (IgG versus anti-CD8, ****P < 0.0001) or anti–CTLA-4_GX plus 7HP349 (IgG versus anti-CD8, **P < 0.01), 1-way ANOVA, Tukey’s test. (E) Correlation analysis of granulocytes, IMs, or M1 macrophages versus CD8+ Teffs from tumors of mice treated with anti–CTLA-4 and 7HP349 or vehicle (n = 6).