LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade
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
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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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 6

Neutrophils are critical for CD8+ Teff antitumor response in 7HP349-treated mice.

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Neutrophils are critical for CD8+ Teff antitumor response in 7HP349-trea...
(See Supplemental Figure 13). Mice bearing 3-day s.c. B16-BL6 melanomas received anti–CTLA-4 therapy and 7HP349 or vehicle and/or anti-Ly6G mAb or IgG, as indicated. (A) Experimental schematic. (B) Flow cytometry analysis showing anti-Ly6G mAb depletion of neutrophils at day 5 in PBMCs. FSC-A, forward scatter–A; FSC-H, forward scatter–H. (C) Average tumor burden in mice (n = 10) after IgG or anti-Ly6G treatment. Data are represented as mean ± SEM.One-way ANOVA, Tukey’s test. *P < 0.05; **P < 0.01. (D) Frequency of CD8+ or CD4+ Teffs and Tregs, adjusted per tissue weight (mg–1) in mice after IgG or anti-Ly6G treatment (n = 6). (E) CD8+ Teff/Treg and CD4+ Teff/Treg ratios following IgG or anti-Ly6G treatment (n = 6). (F) Frequency of IMs, M1 macrophages, pDC, cDC1, and cDC2 adjusted per tissue weight (mg–1) in mice after IgG or anti-CXCL12 treatment (n = 6). (G) cDC2/Tregs, cDC2/M2 macrophage, cDC2/granulocyte, or cDC2/monocyte ratios after IgG or anti-Ly6G treatment (n = 6). (H) Immune cell sequestration fold increase at the TME after IgG or anti-Ly6G treatment (n = 5). Data are represented as mean ± SEM. Data analyses (D–G) were performed using unpaired t test. *P < 0.05.