Tumor microenvironment noise-induced polarization: the main challenge in macrophages' immunotherapy for cancer

Abstract

Disturbance of epigenetic processes can lead to altered gene function and malignant cellular transformation. In particular, changes in the epigenetic landscape are a central topic in cancer biology. The initiation and progression of cancer are now recognized to involve both epigenetic and genetic alterations. In this paper, we study the epigenetic mechanism (related to the tumor microenvironment) responsible for increasing tumor-associated macrophages that promote the occurrence and metastasis of tumor cells, support tumor angiogenesis, inhibit T-cell-mediated anti-tumor immune response, and lead to tumor progression. We show that the tumor benefits from the macrophages' high degree of plasticity and larger epigenetic basins corresponding to phenotypes that favor cancer development through a process that we call noise-induced polarization. Moreover, we propose a mechanism to promote the appropriate epigenetic stability for immunotherapies involving macrophages, which includes p53 and APR-246 (eprenetapopt). Our results show that a combination therapy may be necessary to ensure the proper epigenetic stability of macrophages, which otherwise will contribute to cancer progression. On the other hand, we conclude that macrophages may remain in the anti-tumoral state in types of cancer that exhibit less TP53 mutation, like colorectal cancer; in these cases, macrophages' immunotherapy may be more suitable. We finally mention the relevance of the epigenetic potential (Waddington's landscape) as the backbone for our study, which encapsulates the biological information of the system.

Keywords: Cancer immunology; Epigenetics; Macrophage polarization; Random perturbations; Tumor Microenvironment.

Fig. 1

Heat Map of Transcription Factor Overexpression and Knockout (based on Fig. 3 [6]). A Heat map showing the effects of transcription factor overexpression on macrophage polarization. B Heat map illustrating the impact of transcription factor knockouts on macrophage polarization. Green regions represent attractors with an increased basin size following the perturbation, while red regions denote those with a decreased basin size. Black indicates attractors with minimal changes in basin size compared to the wild-type (WT) after perturbation. Gray areas represent attractors present in the WT that disappear upon perturbation

Fig. 2

Macrophages’ epigenetic potential (Waddington’s landscape) in 3D (top) and the corresponding contour representation (bottom). The figure at the bottom shows the locations of the thirteen types of macrophages (phenotypes) in the epigenetic landscape, where each dot is the center of a phenotype, and the contours represent the depth of each phenotype (dark blue corresponds to the deepest region). In what follows, we use the contour representation of the epigenetic potential

Fig. 3

Evolution of the epigenetic state of a macrophage (in white) starting at the M1 phenotype center, up to t units of time, and subjected to different noise magnitudes, $\sigma$, representing the stages of the TME: the higher the value of $\sigma$, the more advanced the tumor is. The noise (a Brownian process) represents the molecular signals in the TME

Fig. 4

Evolution of the epigenetic state of a macrophage (in white) starting at the M1 phenotype center showing the noise-induced polarization into protumoral phenotypes due to the TME. Each plot shows the system’s dynamics up to t units of time, with fixed $\sigma =0.27$

Fig. 5

Evolution of the epigenetic state of a macrophage (in white) starting at the M0 phenotype center (monocyte), up to t units of time, and subjected to different noise magnitudes, $\sigma$, representing the stages of the TME: the higher the value of $\sigma$, the more advanced the tumor is. The noise (a Brownian process) represents the molecular signals in the TME

Fig. 6

Evolution of the epigenetic state of a macrophage (in white) starting at the M0 phenotype center showing the noise-induced polarization into protumoral phenotypes due to the TME. Each plot shows the system’s dynamics up to t units of time, with fixed $\sigma =0.20$

Fig. 7

Evolution of the epigenetic state of a macrophage (in white) starting at the M1M2bM2cM2d phenotype center, up to t units of time, and subjected to different noise magnitudes, $\sigma$, representing the stages of the TME: the higher the value of $\sigma$, the more advanced the tumor is. The noise (a Brownian process) represents the molecular signals in the TME

Fig. 8

Evolution of the epigenetic state of a macrophage (in white) starting at the M1M2bM2cM2d phenotype center showing the noise-induced polarization. Each plot shows the system’s dynamics up to t units of time, with fixed $\sigma =0.25$

Fig. 9

The effect of p53 on the epigenetic evolution of macrophages in a TME. Left: p53 stabilizes the epigenetic M1 state. Right: in the absence of an epigenetic stabilizer, the macrophage polarizes into a protumoral state