Combinatorial Approaches with Checkpoint Inhibitors to Enhance Anti-Tumor Immunity as Advantages of Targeting the Tumor Immune Microenvironment over Blocking Immune Checkpoint in Cancer Immunotherapy

Abstract

Aging is a condition in which the cell cycle is essentially irreversible and is caused by a variety of stressors such as obesity, radiation and chemotherapy. Aging cells that accumulate in the body during this period communicate with surrounding tissues through the production of proinflammatory proteins, called the SASP, and play a number of physiological and pathological roles. In the elderly, inflammatory agents of SASP increase various age-related diseases, including cancer; therefore, clarification of the SASP monitoring mechanism is essential for the development of new prevention and treatment strategies against age-related cancer. A group of Cancer Research Institute (CRI) of California South University researchers have hypothesized that the abnormal chromatin architecture observed in aging cells is related to SASP, and have begun analyzing chromatin interaction at the genome level and gene expression using next-generation sequencing techniques. They showed that the region containing the pericentromeric repetitive sequences called Human Satellite II (hSATII), which is genetically inactive in normal cells, has a significant state in aging cells; In addition, non-coding RNA expression (hSATII RNA) was significantly regulated during cellular aging. Further analysis showed that hSATII RNA regulated the expression of SASP-like inflammatory genes by disrupting chromatin interactions in some regions of the SASP gene through dysfunction of the CCCTC-binding factor (CTCF), which is important for maintaining genomic integrity. Small extracellular vehicles (EVs) secreted by cancer cells and stromal cells are dynamically involved in the development and progression of non-cellular tumors in the tumor microenvironment, and surprisingly more than the amount of hSATII RNA in small EVs caused by aging cells. Thus, our data suggest that hSATII RNA derived from aging stromal cells is transported to surrounding cells via small EVs and acts as an SASP-like inflammatory agent in the tumor microenvironment. In addition, the researchers found that hSATII RNA could be detected in cancer cells in surgical specimens of patients with primary colon cancer. Significantly, the population of hSATII-positive RNA cells was higher among cancer-associated fibroblasts than in fibroblasts in normal stromal tissues. These findings demonstrate the new role of hSATII RNA, which supports non-cellular tumor growth by secreting inflammatory agents similar to SASPs and small EVs. Understanding this molecular mechanism could facilitate new preventive and therapeutic development and provide solutions for future age-related injuries. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening; Treatment; Management