Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

Abstract

Background: Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined.Methods: T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype.Conclusion: Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

“…The combination of epigenetic therapy and immunotherapy is being intensively investigated, and novel trials will be needed to elucidate this role as adjunctive therapy. Epigenetic inhibitors are able to reverse or overcome immune resistance to immunotherapy treatment through upregulation of chemokine expression, antigen processing and presentation machinery, and immune checkpoint molecules [ 241 ]. As such, the rationale is that the epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy.…”

Immune Checkpoints in Pediatric Solid Tumors: Targetable Pathways for Advanced Therapeutic Purposes

“…As already mentioned, during cancer progression a "cancer immune-editing", based on three different phases, elimination, equilibrium and escape, takes place [20]. In the last phase, T lymphocytes become exhausted or tolerized, due to chronic antigen stimulation and the up-regulation of different inhibitory receptors [90]. The most characterized IC are the co-inhibitory molecules CTLA-4, PD-1 and its ligands PD-L1/2 [91], lymphocyte activating antigen-3 (LAG-3) [92], T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) [93] and T cell immune-receptor with Ig and ITIM domains (TIGIT) [94].…”

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

“…Even though the administration of immune checkpoint inhibitors described in the previous section have successfully reversed the immunosuppressive mechanism by cancer cells in some cases, however, a substantial number of cases still did not show tumor regression or, at most, only a temporary tumor regression. This persistent immune tolerance is due to the proliferation of dysfunctional to exhaustive T cells within the tumor microenvironment [ 43 , 44 , 45 ]. An in-depth study analyzing the transcriptome of every single immune infiltrating lymphocytes in melanoma samples revealed that majority of CD8+ T cells were indeed lacking a complete cytotoxic gene expression, thus making them dysfunctional [ 43 ].…”