Abstract
Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and γδ T cells that recognize NKG2DL is limited by the drug’s concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O6-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified γδ T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.
Highlights
Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL)
We have previously shown that resistance to alkylating agents can be conferred to T cells and NK cells by genetically modifying these effectors to express AGT from an methylguanine DNA methyltransferase (MGMT) transgene[12,15,16] allowing full function at therapeutic concentrations of chemotherapy
The γδ T cells are transduced during culture with a P140K-MGMT expressing lentivirus
Summary
Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). In addition to reducing tumor mass, thereby reverting T cell exclusion and promoting T cell infiltration[9], chemotherapy can generate pro-inflammatory T cell and myeloid cytokine e xpression[10] Alkylating agents such as Temozolomide (TMZ), the primary chemotherapeutic agent for glioblastoma (GBM), methylates the O6 position of guanine residues thereby inducing mispairing with thymine during replication inducing cascading cycles of thymine excision and reinsertion, DNA strand breaks, and activation of the DNA damage response leading to cytotoxicity. The lymphodepleting properties of chemotherapy dampen an effective cellular immune response at the time of the tumor’s greatest v ulnerability[12,14] To counter this problem, we have previously shown that resistance to alkylating agents can be conferred to T cells and NK cells by genetically modifying these effectors to express AGT from an MGMT transgene[12,15,16] allowing full function at therapeutic concentrations of chemotherapy. This approach incorporates TMZ–induced upregulation of NKG2DL expression and simultaneous targeting with MGMT-modified γδ T cells
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