**18. Epigenetic therapy drugs boost immune attraction properties of epithelial cancer cells**

Immunotherapy has presently become a remarkable tool to employ immune cells in tumor management. Blocking immune checkpoints to stimulate and retore immune response in the tumor immune suppressive microenvironment has showed robust clinical response. However, several patients tend to remain unresponsive towards immune checkpoints blockades. Epigenetic therapy using DNMTis and HDACis have showed potential in immune modulation properties of tumor cells and immune cells, thereby suggesting a rationale for integrating epigenetic with immunotherapy.

It is well known that cytotoxic T cells (Tc) are requisite for an anti-cancer immune response and immune check point blockade. This mechanism relies on antigen presenting cells and the quantity of antigens presented to Tc cells. Also, tumors with high mutations show robust response to immune check point blockade due to high presence of neo-antigens presented to Tc cells [125, 126]. Several studies demonstrate that high immunogenicity is followed by exposure to epigenetic therapy. DNTMis have been found to upregulate and augment expression of cancer testis antigens (CTAs) such as MAGE-A1 and NY-ESO-1 [127]. Besides, exposure to epigenetic therapy viz. HDACis and DNMTis also upregulated antigen presenting and processing related genes such as b2-microglobulin, Human leukocyte antigen (HLA)-class I genes, and TAP1 in solid tumors [128, 129]. Furthermore, it was revealed that HDAC inhibitors stimulate human endogenous retroviruses (HERVs) reactivation, which induce activation of pattern recognition receptors and a type I/III interferon response thereby enhancing antigen presentation to Tc cells [129, 130]. Together, these results paint the picture that epigenetic therapy using HDACis and DNMTis augment presentation of CTA and HERV-derived antigens, thus enhancing immune response in low mutation therapy [131]. In AML patients, epigenetic therapy with DNMTis promoted robust T cell mediated immune response by reactivation of CTAs [132]. The host immune system recognizes the CTAs with high affinity, they represent good candidates for immunotherapy, including vaccines. There is thus great potential for DNMT inhibitor treatment to upregulate CTAs on tumors, facilitating targeting by the host immune system [133]. Guo et al. demonstrated that exposure of 4T1 mammary carcinoma cells in syngeneic mice to DNMTi 5-aza-2-deoxycytidine induced demethylation and upregulation of CTA P1A. Also, the upregulated P1A was targeted by P1A–specific T cells, and combined therapy with 5- aza-20-deoxycytidine and adoptive transfer of these T cells significantly reduced lung metastases in this mouse model [134].

Additionally, synergistic relation was observed in pre-clinical models of diffuse large B cell lymphomas for combinatorial exposure to DNMTis and HDACis [135]. Increasing evidence suggests that tumors possess variable numbers of infiltrated immune cells and the quantity, type, and location of infiltration can help in predicting response to immune check point blockade [36, 136]. It is now well established that epigenetic therapy with modulates directly infiltration of immune cells in

#### *Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.100183*

tumor stroma. DNMTi treatment in addition to inhibiting tumor progression, increased infiltration of CD8+ T cell infiltration, and natural killer (NK) cells and reduced infiltration of immune-suppressive cells [131, 137]. Also, HDACis treatment in combination with DNMTis activates chemokine signaling networks and augments infiltration of cytotoxic T cells [138]. In preclinical studies, treatment with romidepsin, the pan-HDAC inhibitor, augmented expression of chemokines by tumor cells which elevated infiltration of T cells into the tumor stroma and reduced tumor growth by robust immune response [139].

Accumulating evidence from preclinical models of diverse solid tumors viz. breast, melanoma and colorectal cancer, revealed that combining immune check point inhibitors such as anti-CTLA4 or anti-PD1 with epigenetic therapy (DNMTis and HDACis) augmented antitumor response and reduced tumor growth and response to immunotherapy than using monotherapy of either agent [122, 136]. Also, combinational treatment with DNMTis and anti-CTLA4 antibody enhanced chemokine expression and increased survival of mice with orthotopic or subcutaneous tumors [137].

Together, these results paint the picture that combining immunotherapy with combinational therapy, greatly enhances antitumor immune responses, by augmented expression of chemokines and these act in a synergistic manner. Also, multiple clinical trials are currently testing the combination of DNMTi or HDACi with various immune check point inhibitors (**Table 7**).
