Tackling tumor microenvironment through epigenetic tools to improve cancer immunotherapy

Abstract

Background: Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage.

Main body: Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy.

Conclusion: Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Keywords: Bladder cancer; Epigenetics; Immunotherapy; Therapy; Tumor microenvironment.

Fig. 1

DNA methylation, histone modifications and chromatin remodeling as regulatory mechanisms of epigenetic gene regulation. DNA methylation represents a process by which methyl groups are transferred onto the 5′ position of a cytosine molecule, commonly in the context of CpG sites, without altering the DNA sequence. Histone modifications include post-translational modifications at the histone N-terminal tails, such as acetylation, methylation and phosphorylation, causing chromatin structure alterations. Changes in nucleosome position are also responsible for rearrangement of chromatin structure, a process known as chromatin remodeling. Nucleosomes can be affected in several ways, including nucleosome sliding, nucleosome ejection and histone eviction. Histone variants add further complexity to epigenetic regulation of the genome. Various histone variants are characterized for H2A, H2B and H3. All these mechanisms are highly interrelated and play an important role in the regulation of gene accessibility to the transcriptional machinery

Fig. 2

Epigenetic regulation of immune cells in the tumor microenvironment. Decreased KLF4 and increased SATB1 expression affect IL-6 (upregulation) and Galectin (downregulation) expression, remodeling anti-tumor DCs into pro-tumor DCs. MDSCs expansion, accumulation and recruitment are favored by STAT3-induced expression of immunosuppressive factors S100A8, Arg1 and S100A9. In this cell population, STAT3 expression is controlled by DNMTT3a/b, HDAC6 and HDAC11. Macrophages can convert into TAMs under the influence of multiple epigenetic factors, including DNMT3b, PRMT1, HDAC3/4, HDAC9 and SIRT2, favoring acquisition of the M2 phenotype through various pathways, such as increased PPARγ and Arg1 expression as well as downregulation of inflammatory factors TNF-α and IL-1β. SMYD3 activates M2 marker ALOX15. Impaired NK-cell anti-tumor cytotoxicity can be the result of increased EZH2 expression, which downregulates activating NK-cell receptor NKG2D through enhanced H3K27me3 levels. The same way, EZH2 also regulates inhibition of regulatory T-cell pro-inflammatory activities. Naïve CD8 + T-cells differentiate into TILs or exhausted CD8 + cells dependent on epigenetic profile. Whereas specific DNA methylation patterns of CTLA4, PDCD1 and LAG3 are identified in exhausted CD8 + T-cells, DNMT1 and EZH2 inhibit CD8 + TILs infiltration through downregulation of CXCL9 and CXCL10 chemokines. TGF-β and SATB1 affect TILs infiltration by controlling PD-1 expression. DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; NK, natural killer; Tregs, regulatory T-cells; TILs, tumor-infiltrating lymphocytes

Fig. 3

Modalities of immunotherapy in bladder cancer. BCG is a weakened strain of Mycobacterium bovis and was the first of immunotherapy approved for BC. NMIBC patients with high risk of recurrence are subjected to BCG therapy. The administration of BCG leads to a stimulation of both adaptative and innate immune response by recruiting lymphocytes, macrophages, NK cells and neutrophils, leading to the elimination of the remaining tumor cells. On the other hand, BC patients with MIBC are candidates for immune checkpoint blockage. Tumor cells express repression signals that lead to the inhibition of the immune response, namely by expressing PD-L1/PD-L2 and B7-1/B7-2, that will bind to PD-1 and CTLA-4 present in T lymphocytes, respectively. Nevertheless, with the administration of antibodies against PD-1, PD-L1 or CTL4-A, this process is reverted, leading to the activation of T cells and the start of an immune response against tumor cells, leading ultimately to their death