After decades of unfulfilled promise, immunotherapies for cancer have finally reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC Class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC Class I expression in pediatric cancers including a discussion of prognostic significance, the opposing influence of MHC on T-cell versus NK-mediated therapies, and strategies to reverse or circumvent MHC down-regulation.
Protein farnesyltransferase (FTase) catalyzes the post-translational modification of many important cellular proteins, and is a potential anticancer drug target. Crystal structures of the FTase ternary complex illustrate an unusual feature of this enzyme, the fact that the isoprenoid substrate farnesyl diphosphate (FPP) forms part of the binding site for the peptide substrate. This implies that changing the structure of FPP could alter the specificity of the FPP-FTase complex for peptide substrates. We have found that this is the case; a newly synthesized FPP analogue, 3-MeBFPP, is a substrate with three peptide cosubstrates, but is not an effective substrate with a fourth peptide (dansyl-GCKVL). Addition of this analogue also inhibits farnesylation of dansyl-GCKVL by FPP. Surprisingly, the differential substrate abilities of these four peptides with FPP-FTase and 3-MeBFPP-FTase complexes do not correlate with their binding affinities for these isoprenoid-enzyme complexes. The possible mechanistic rationales for this observation, along with its potential utility for the study of protein prenylation, are discussed.
Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform.
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