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

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

doi:10.1016/j.celrep.2021.110021

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

Cell Rep. 2021 Nov 23;37(8):110021. doi: 10.1016/j.celrep.2021.110021.

Authors

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA.
³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: [email protected].

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.

Keywords: NK cell; checkpoint blockade; interleukin-2; macrophage; sensitization; tumor microenvironment; tumor-targeting antibody; vascular normalization.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies
Cell Line, Tumor
Humans
Immune Checkpoint Inhibitors / immunology
Immunotherapy / methods*
Interleukin-2 / pharmacology
Killer Cells, Natural / metabolism*
Macrophages / immunology
Macrophages / metabolism*
Mice
Mice, Inbred C57BL
Neoplasms / drug therapy
Neoplasms / immunology*
Programmed Cell Death 1 Receptor / metabolism
Tumor Microenvironment / immunology

Substances

Antibodies
Immune Checkpoint Inhibitors
Interleukin-2
Programmed Cell Death 1 Receptor

Abstract

Publication types

MeSH terms

Substances

Grants and funding