Park et al. demonstrated that adoptively transferred, ex vivo-activated, antigen-pulsed macrophages (M_ther) elicited robust systemic and local antitumor immune responses in both subcutaneous and lung metastasis melanoma models. M_ther treatment activated antigen-specific CD8+ T cells, CD4+ T cells, and NK cells, and promoted antitumor cytokine production. M_ther activation also facilitated splenic DC and NK cell activation, while antigen-presenting functions triggered CD8+ T cell responses. The antitumor immune effects of M_ther were dependent on NK and CD8+ T cells, but not on CD4+ T cells.
Contributed by Shishir Pant
Background: Macrophages have been classically associated with their innate immune functions of responding to acute injury or pathogenic insult, but they have been largely overlooked as primary initiators of adaptive immune responses. Here, we demonstrate that adoptively transferred macrophages, with optimal activation prior to administration, act as a potent cellular cancer therapeutic platform against a murine melanoma model.
Method: The macrophage therapy was prepared from bone marrow-derived macrophages, pretreated ex vivo with an activation cocktail containing interferon-γ, tumor necrosis factor-α, polyinosinic:polycytidylic acid, and anti-CD40 antibody. The therapy was administered to tumor-bearing mice via the tail vein. Tumor growth and survival of the treated mice were monitored to evaluate therapeutic efficacy. Tumors and spleens were processed to examine immune responses and underlying mechanisms.
Results: This immunotherapy platform elicits systemic immune responses while infiltrating the tumor to exert direct antitumor effects in support of the systemic adaptive response. The macrophage-based immunotherapy produced a strong CD8+T cell response along with robust natural killer and CD4+T cell activation, inducing a "hot" tumor transition and achieving effective tumor suppression.
Conclusions: Owing to their inherent ability to home to and infiltrate inflamed tissues, macrophage-based cancer immunotherapies exhibited a unique in vivo trafficking behavior, efficiently reaching and persisting within tumors. Macrophages orchestrated a multiarmed immune attack led by CD8+T cells, with the potential for local, intratumoral activation of effector cells, demonstrating a novel cancer immunotherapy platform with meaningfully different characteristics than clinically evaluated alternatives.
Author Info: (1) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massa
Author Info: (1) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. (2) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. (3) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (4) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. (5) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (6) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. (7) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. (8) Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, Massachusetts, USA. Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts, USA. (9) John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, Massachusetts, USA mitragotri@seas.harvard.edu. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts, USA.
