The Sentinel


Monday, November 11, 2019

SITC 2019 Scientific Highlights - Nov. 10

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 10, 2019, sessions of the 34th Annual Meeting.

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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