Harnessing the innate immune system by revolutionizing macrophage-mediated cancer immunotherapy

Abstract

Immunotherapy is a promising and safer alternative to conventional cancer therapies. It involves adaptive T-cell therapy, cancer vaccines, monoclonal antibodies, immune checkpoint blockade (ICB), and chimeric antigen receptor (CAR) based therapies. However, most of these modalities encounter restrictions in solid tumours owing to a dense, highly hypoxic and immune-suppressive microenvironment as well as the heterogeneity of tumour antigens. The elevated intra-tumoural pressure and mutational rates within fastgrowing solid tumours present challenges in efficient drug targeting and delivery. The tumour microenvironment is a dynamic niche infiltrated by a variety of immune cells, most of which are macrophages. Since they form a part of the innate immune system, targeting macrophages has become a plausible immunotherapeutic approach. In this review, we discuss several versatile approaches (both at pre-clinical and clinical stages) such as the direct killing of tumour-associated macrophages, reprogramming pro-tumour macrophages to anti-tumour phenotypes, inhibition of macrophage recruitment into the tumour microenvironment, novel CAR macrophages, and genetically engineered macrophages that have been devised thus far. These strategies comprise a strong and adaptable macrophage-toolkit in the ongoing fight against cancer and by understanding their significance, we may unlock the full potential of these immune cells in cancer therapy.

Figure 1

Types of macrophages: the proinflammatory and anti-tumourigenic M1 (classically activated) and the anti-inflammatory and pro-tumourigenic M2 (alternatively activated) phenotypes. M1 phenotypes are induced by LPS, IFN-γ, and TNF-α, and they are characterized by the expression of TLR-2, TLR-4, CD86, CD80, iNOS, and MHC-II. Once activated, M1 macrophages release various cytokines and chemokines, such as TNF-α, IL-1α, IL-1β, IL-6, IL-12, CXCL9, and CXCL-10. Transcription factors NF-κB, STAT1, STAT5, IRF3, and IRF-5, and HIF-α regulate the expression of M1 marker genes. IL-4 and IL-13 directly induce polarization into M2 phenotype, which is identified by the expression of FIZZ1, CD206, CD209, Ym1/2, and CD163, and the secretion of TGF-β, IL-10, CCL1, CCL17, CCL18, CCL22, CCL24, CXCL13, and VEGF.

Figure 2

Contribution of TAMs to tumour progression and strategies to target them. In the TME, TAMs deactivate T cells, promote tumour angiogenesis, and induce T_reg activity, all of which support tumour growth and subsequent metastasis. TAM targeting strategies consist mainly of inhibition of monocyte recruitment, developing engineered macrophages, TAM reprogramming, and depleting TAM populations.

Figure 3

Mechanism of action of CAR-M. (1) Once the CAR-M comes into contact with the specific target antigen on tumour cells, it leads to phagocytosis of the tumour cells (2, 3) and presentation of the tumour antigens to T cells, thereby activating them (6). The tumour phagocytosis also activates transcription factors such as NF-κB, etc. (4) leading to subsequent release of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12, etc. (5). These eventually lead to infiltration of NK, dendritic cells, and TILs into the TME, where the presence of TNF-α, IL-6, IL-12, etc. results in a pro-inflammatory TME, thereby facilitating tumour clearance.