Role of Sirt2 in T cell activity elucidated
Sirt2 inhibition enhances anti-tumor immunity by promoting T cell metabolism
Abstract O51
Imene Hamaidi, PhD – Moffitt Cancer Center
A possible mechanism for improving anti-tumor immune
responses was proposed by Dr. Imene Hamaidi (Moffitt Cancer Center). The role
of Sirt2 in immune responses is debated; therefore, this study aimed to
elucidate its role in T cell metabolism and function, using murine studies and
ex vivo analysis of T cell activity, metabolites, and other immune markers.
In mouse models, Sirt2 deficiency led to a hyper-reactive T
cell phenotype, which endowed these mice with an increased capacity to reject engrafted
tumors. Similarly, Sirt2-/- T cells exhibited improved anti-cancer activity and
hypermetabolism. Upon T cell activation, Sirt2 was observed to interact
directly with PFKP, GAPDH, enolase, and aldolase glycolytic pathway enzymes,
and modified their activity. Through analysis of tissue samples from clinical
trials, patients with increased Sirt2 expression in their TILs were found to
have poorer responses to immunotherapy, providing more support to the
preclinical studies. Inhibition of Sirt2 pharmacologically increased the
effector capacity of human T cells in culture as well. Therefore, the Sirt2
pathway warrants further investigation to improve outcomes to immunotherapy
treatments.
Genetic markers for TIL responsiveness identified
The road-map to tumor-infiltrating lymphocyte (TIL) therapy: Understanding genetic alterations for improved patient treatment
Abstract O5
Caitlin Creasy, MS – MD Anderson Cancer Center
Biomarkers for response to TIL therapy in melanoma were
presented by Caitlin Creasy, MS (MD Anderson Cancer Center). Pre-treatment
tumor tissue samples were analyzed using whole exome (WES) and RNA sequencing and
immunohistochemistry to generate correlations with treatment response,
progression-free survival, and overall survival.
Overall survival, but not PFS or response, could be
predicted from WES results, with a higher neoantigen burden indicative of
longer survival. Two genetic mutations were enriched in the overall patient
cohort – KCNQ2 and SFTA3. These mutations occurred at a rate higher than that
observed in TCGA (1.9 vs 13% and 0.6 vs 6%, respectively), which the authors
hypothesized to be a result of the higher-stage cohort in this study relative
to the TCGA population. Samples from recurring tumors did not indicate any driver
mutations, but changes in the abundance of tumor subclones were observed. From
RNAseq, three genes were found to correlate with better outcomes: PDE1C, RTKN,
and NGFR; at the same time, ELFN1 was enriched in patients with worse outcomes.
Recurrent tumors were found to have markers of a mesenchymal phenotype as well.
This study therefore presents possible biomarkers for response, as well as
possible pathways of immune escape.
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