Immunoresistant metastatic tumor variants can re‐express their tumor antigen after treatment with DNA methylation‐inhibiting agents

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Abstract
Immuno‐escaping variants which arise during metastasis of ESb lymphoma cells in syngeneic DBA/2 mice have been shown to exhibit selective resistance to lysis by ESb‐specific cytotoxic T‐lymphocytes (CTL). The immuno‐resistant variants present no changes in the expression of H‐2Kd molecules which appear to be the restricting elements for ESb‐specific CTL. We now show that treatment of clonal immuno‐resistant ESb variant cells with MNNG or 5′azacytidine can restore the sensitivity to tumor‐specific CTL lysis in a high percentage of cloned progenitor cells. The acquisition of susceptibility to lysis by these clones is most likely due to re‐expression of ESb‐type tumor antigens because such cells (i) regain the capacity to compete with original 51Cr‐labelled ESb cells for lysis by ESb‐specific CTL, and (ii) regain the capacity to induce ESb‐specific CTL in vivo. Our data suggest that the immuno‐resistant variants are not cellular mutants but rather gene regulatory variants. This could explain: (i) their high frequency of occurrence during metastasis; (ii) the relative stability of the variant phenotype; and (iii) the reversibility observed after the use of DNA‐demethy‐lating and gene‐activating drugs like 5′‐azacytidine or MNNG.