Targeting of TAMs: can we be more clever than cancer cells?

Abstract

АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.

Keywords: Angiogenesis; Cytokine; Epigenetic; Growth factor; Immunotherapy; Metabolism; Scavenger receptor.

Fig. 1

Clinical significance of TAMs. For the majority of TAM biomarkers, their correlation with unfavorable prognosis has been demonstrated for solid cancers. In contrast to other cancers, in colorectal cancer, CD68 (panmacrophage marker) is positively correlated with favorable patient prognosis. Individual TAM biomarkers are illustrated by different color coding. Filled macrophage icons are used as biomarkers for scavenger receptors. Сontoured macrophage icons are used as other TAM biomarkers. The orange background covers macrophage subtypes that correlate with a negative prognosis or with the inhibition of anticancer therapy efficacy. The blue background covers TAM subtypes that correlate with a favorable prognosis and TAMs that cooperate with anticancer therapy

Fig. 2

Functions and mediators of TAMs in tumor progression. Both resident macrophages and monocyte-derived macrophages can be involved in tumor initiation. Low-grade chronic inflammation drives genomic instability in cells. After the transformed cells escape immune control by macrophages, the growing cancer cell clones start recruiting blood monocytes. Other steps of tumor progression are controlled to a greater extent by monocyte-derived TAMs. TAMs secrete diverse protumor mediators (yellow boxes), which control many processes (gray boxes). TAMs are able to form an immunosuppressive microenvironment to facilitate angiogenesis and lymphangiogenesis, activate molecular mechanisms accompanying tumor invasion and intravasation, support cancer cell survival in the bloodstream, and help to form a premetastatic niche. Many open questions remain regarding the precise mechanisms involved in the generation of circulating clusters consisting of circulating tumor cells (CTCs) and TAMs as well as the role of TAMs in premetastatic niche formation

Fig. 3

Mechanisms of CAR-macrophage-mediated targeting of cancer cells. CAR-T cells recognize and bind to target molecules on the cancer cell surface, that triggers intracellular signaling, including NF-kB, STAT3, and JAK. The primary effect of CAR-T cells is phagocytosis of cancer cells and their elimination. The additional effect is M1 polarization of TAMs, which involves elevated expression of CD80 and CD86 and increased secretion of proinflammatory cytokines, stimulating the cytotoxic T-cell response