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  • Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

Cell reports (2021-11-25)
Chensu Wang, Ang Cui, Maurice Bukenya, Aereas Aung, Dikshant Pradhan, Charles A Whittaker, Yash Agarwal, Ayush Thomas, Simon Liang, Parastoo Amlashi, Heikyung Suh, Stefani Spranger, Nir Hacohen, Darrell J Irvine
ABSTRACT

Treatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
FTY720, ≥98% (HPLC)
Sigma-Aldrich
4-Hydroxytamoxifen Ready Made Solution, 5 mg/mL in ethanol: isopropanol (95:5)
Roche
DNase I, grade II, from bovine pancreas
Sigma-Aldrich
Anti-NG2, Alexa Fluor488 Conjugate Antibody, from rabbit, ALEXA FLUOR 488