Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment

Abstract

Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.

Determinants and Functions of CAFs Secretome During Cancer Progression and Therapy

“…CAF phenotype may be driven by epigenetic deregulation rather than by somatic mutations (Qiu et al, 2008;Bianchi-Frias et al, 2016;Pidsley et al, 2018). DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAmicro RNA (miRNA) and long non-coding RNA (lncRNA)-are the well-described molecular mechanisms behind the epigenetic CAF reprogramming and have been thoroughly reviewed elsewhere (Marks et al, 2016;Melissari et al, 2020;Pan and Zheng, 2020). Interestingly, several studies support the hypothesis that an epigenetic switch would initiate the activation process leading to a stable CAF cell state with tumor-supportive secretory phenotype (Albrengues et al, 2015;Kalluri, 2016).…”

Enriched cancer stem cells, dense stroma, and cold immunity: Interrelated events in pancreatic cancer

“…[ 5 ] The position of the pancreas within the body, which is almost inaccessible for routine evaluation, along with the unreliability of symptoms and biomarkers (lack of sensitive screening methods for early diagnosis) and the inherent metastatic nature of this cancer type are proposed to play an important part in the blame, switching the condition into lesions unable to resect surgically in more than 85% of cases. [ 1,3,12,14 ] In fact, patients with pancreatic cancer generally show clinical symptoms specific to this cancer type very late in time, which will make it difficult to have interventions at earlier stages. [ 14 ]…”

“…[ 17 ] For pancreatic cancer, CAFs occupy about 90% of the whole tumor mass. [ 3 ] CAFs are heterogeneous genetically, phenotypically, and functionally. High fibroblast activating protein (FAP) + CAFs are involved in ECM remodeling and are found in the low ECM stiffness areas, while ɑ‐smooth muscle actin (α‐SMA) + CAFs contribute to the ECM contraction and can be found in the high ECM stiffness regions.…”

“…[ 28 ] CAFs in an activated form has three subtypes: inflammatory (iCAFs), myofibroblastic (myCAFs), and antigen‐presenting (apCAFs) cells. [ 3 ] In pancreatic cancer, iCAFs and myCAFs are the two most common subtypes, [ 3 ] both of which are protumorigenic. The iCAFs exert pro‐proliferative effects, and the myCAFs contribute to the production of the surrounding stroma.…”

“…The myCAF subtype seems to act for induction of CSCs possibly via secretion of osteopontin (which acts via interaction with integrin αvβ3). [ 3 ] The activity of CAFs in potentiating the fraction of CSCs is more evident in patients receiving chemotherapy. This is performed to strengthen resistance within the TME, taking advantage by promoting tumor relapse.…”