CTL Adoptive Immunotherapy Concurrently Mediates Tumor Regression and Tumor Escape

Abstract

Tumor escape and recurrence are major impediments for successful immunotherapy. It is well-documented that the emergence of Ag-loss variants, as well as regulatory mechanisms suppressing T cell function, have been linked to inadequate antitumor activity. However, little is known regarding the role of Fas-mediated cytotoxicity by tumor-specific CD8+ CTL in causing immune evasion of Fas resistant variants during adoptive immunotherapy. In this study, we made use of an adoptive transfer model of experimental lung metastasis using tumor-specific CTL as a relevant immune-based selective pressure, and wherein the Fas ligand pathway was involved in the antitumor response. Surviving tumor cells were recovered and examined for alterations in antigenic, functional, and biologic properties. We showed that diminished susceptibility to Fas-mediated cytotoxicity in vivo was an important determinant of tumor escape following CTL-based immunotherapy. Tumor escape variants (TEV) recovered from the lungs of CTL-treated mice exhibited more aggressive behavior in vivo. However, these TEV retained relevant MHC class I and tumor Ag expression and sensitivity to CTL via the perforin pathway but reduced susceptibility to Fas-mediated lysis. Moreover, TEV were significantly less responsive to eradication by CTL adoptive immunotherapy paradigms as a consequence of increased Fas resistance. Overall, we identified that Faslow-TEV emerged as a direct consequence of CTL-tumor interactions in vivo, and that such an altered neoplastic Fas phenotype compromised immunotherapy efficacy. Together, these findings may have important implications for both tumor progression and the design of immunotherapeutic interventions to confront these selective pressures or escape mechanisms.

Targeting Lymphotoxin β Receptor with Tumor-Specific T Lymphocytes for Tumor Regression

“…Treatment of tumor-bearing mice by CTL adoptive transfer was conducted as previously described (23). To inactivate endogenous host immune cells, mice were irradiated in a Gammacell 40 Exactor Radiator (Nordion International) for a total dose of 5 Gy.…”

“…Spleen-derived CD8 + CTL lines were maintained and propagated in 24-well plates (2 Â 10 Cytotoxicity assay. CTL activity was assessed by 51 Cr release assays as previously described (23). To analyze the role of LThR, lytic assays were done in the absence or presence of anti-LThR mAb (clone AC.H6; PharMingen).…”

How tumours escape mass destruction

“…These studies revealed that antitumour CTL responses in vivo can concurrently mediate tumour regression and tumour progression through the selection and outgrowth of residual Fas lo variants that possess enhanced malignant potential. In fact, such Fas lo variants were not only more aggressive in vivo, but also significantly more refractory to CTL-adoptive immunotherapy (Liu et al, 2005b(Liu et al, , 2006. In addition, in both mouse and human solid tumour models, it was demonstrated that biological selection against Fas-responsive cells within parental or primary tumour cell lines, using surrogate sources of Fas engagement, generated Fas lo sub-populations with enhanced malignant ability (Liu et al, 2003;Liu and Abrams, 2003a (Liu et al, 2005a).…”

“…Several studies have examined whether an antitumour CD8 þ CTL response actually 'selects' such neoplastic sub-populations with enhanced resistance to Fasinduced death (Liu et al, 2005b(Liu et al, , 2006. These studies revealed that antitumour CTL responses in vivo can concurrently mediate tumour regression and tumour progression through the selection and outgrowth of residual Fas lo variants that possess enhanced malignant potential.…”

“…The potential importance of Fas loss of function in tumour escape and tumour progression reflects two important considerations in cancer biology and tumour immunology: (a) Fas downregulation has been noted in the progression of a range of human malignancies (Keane et al, 1996;Krammer et al, 1998;von Reyher et al, 1998;Owen-Schaub et al, 2000;Worth et al, 2002;Liu et al, 2003;Gordon et al, 2005); and (b) if Fas-mediated cytotoxicity is an important host defense mechanism during the effector phase of the immune reaction and if it becomes compromised, this could lead to the emergence of Fas-resistant (Fas lo ) tumour escape variants with potentially enhanced malignant capabilities. Fas lo variants have been shown to exhibit enhanced tumour growth and reduced sensitivity to CTL-based immunotherapy, as shown in mouse models of experimental lung metastasis (Liu et al, 2005b(Liu et al, , 2006. Ultimately, tumour cells that fail to die, through conventional oncological treatments (that is, radiotherapy, chemotherapy) or experimental immunotherapies, have a clear and distinctive survival advantage to persist, accumulate additional genetic or epigenetic modifications and progress to a more malignantly proficient phenotype.…”