An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

Abstract

Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often “oncogene addicted.” The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4+ T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shut down of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are not only involved in tumor initiation, tumor progression, and immunosurveillance, but are also involved in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

MYC: Master Regulator of Immune Privilege

“…This insight should lead to better therapeutic strategies for cancer. In particular, identifying the specific mechanisms and immune components regulated by MYC and other oncogenes should lead to better experimental strategies to use to restore the immune response against tumors and to remodel the tumor microenvironment [73,74]. …”

Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers

“…Tumour cells are frequently edited to bypass immune surveillance (Casey et al , , ). This occurs either through creating an immunosuppressive environment or by preventing recognition by immune cells (Casey et al , ).…”

“…Tumour cells are frequently edited to bypass immune surveillance (Casey et al , , ). This occurs either through creating an immunosuppressive environment or by preventing recognition by immune cells (Casey et al , ). Importantly, CD47 and CD274 (previously termed Programmed death‐ligand 1, PD‐L1), two immune checkpoint proteins expressed on the surface of tumour cells, are directly controlling the anti‐tumour immune response by inhibiting activated T‐cells (Casey et al , ).…”

A new therapeutic potential for cancers: One CAR with 2 different engines!

“…The immune system plays an essential role in defense against tumor cells so that the patients with compromised or suppressed immune function have an extremely increased incidence of cancer. 1 According to the immune surveillance hypothesis, tumor associated antigens (TAA) are considered as "non-self" by the immune system, and an important function of the immune system is to examine carefully the body for the development of malignancy and to eliminate tumor cells as they arise. 2 The elements of the both innate and adaptive immunity, such as natural killer (NK) cells, NKT cells, macrophages, neutrophils, eosinophils, specific cytotoxic T lymphocytes (CTLs), antibodies and some cytokines exhibit antitumor activity.…”

“…2 The elements of the both innate and adaptive immunity, such as natural killer (NK) cells, NKT cells, macrophages, neutrophils, eosinophils, specific cytotoxic T lymphocytes (CTLs), antibodies and some cytokines exhibit antitumor activity. [1][2][3][4] However, the tumor cells escape from immune recognition/killing by several mechanisms such as down-regulating of MHC class I molecules, losing of tumor antigens, defective death receptor signaling, lacking of costimulation, producing of immunosuppressive cytokines and inducing of suppressive cells. [5][6] Surgery, chemotherapy and radiotherapy have been used for decades as primary strategies for treatment of cancer patients, however, the development of resistance to medication or radiation led to a subsequent incidence of tumor relapse.…”