Transmission of “split anergy” from tumor infiltrating to peripheral NK cells in a manner similar to “infectious tolerance”

According to a new paradigm of carcinogenesis, a tumor arises not from transformed cell, but only from tumor initiating cells called cancer stem cells (CSCs), which can originate from tissue stem cells. CSC are resistant to conventional therapy and after treatment form new tumors and give rise to metastases. Only natural killer (NK) cells are capable of lysing CSCs, but within different tumor types these cells experience a condition known as “split anergy”, whereby the NK cells lose the ability to kill CSCs and being to produce cytokines. As a result, uncontrolled tumor growth arises and tumor stroma accumulates anergic NK cells. We hypothesize that anergic tumor infiltrating NK (TINK) cells transmit their property to naïve NK cells by infecting” them with a state of “split anergy” in a similar manner as T conventional cells are transformed into T regulatory cells during the process of “infectious tolerance”. Anergic TINK cells egress from the tumor stroma via the lymphatic system, where they reach regional lymph nodes and transmit their properties to naïve NK cells, which in turn become anergic toward CSCs and lose immunosurveillance functions. The mechanisms proposed for this hypothesis and the methodological approaches for confirming the idea are presented in this issue.