Fas signaling blockade improves adoptive CD8+ T cell treatment for cancer
Tori Yamamoto1,2, Christopher Klebanoff3, Nicholas Restifo2
1Immunology Graduate Group, University of Pennsylvania; 2Center for Cancer Research, NCI; 3Center for Cell Engineering, MSKCC
T cells harvested from blood or tumor for adoptive T cell therapy of cancer are often comprised of memory and late effector subsets. Most of these T cells express Fas, a TNFR superfamily member and death receptor. Current cell expansion methods further differentiate T cells, increasing Fas expression and resulting in less in vivo persistence and tumor lysis. Previously we demonstrated that less differentiated T cell subsets could mediate better tumor regression. Based on our investigations into the non-apoptotic signals by Fas in naïve CD8+ T cells, we hypothesized that modulation of Fas signaling could control T cell differentiation and allow for ACT tumor treatments with robust, tumor-specific T cells. We found that augmenting Fas signaling in memory T cells using an oligomerized form of Fas ligand (FasL) enhanced cellular differentiation, promoted the loss of IL-2 production and induced apoptosis. Conversely, antibody blockade (anti-FasL) of Fas signaling produced phenotypically and functionally less differentiated T cells, limited the acquisition of a glycolytic metabolism, and led to greater fold expansion. Using mice expressing a mutated form of Fas, we found that Fas-mediated differentiation occurs in the absence of death signaling. Using the Pmel-1 CD8+ TCR transgenic model, we found that Pmel-1 memory T cells cultured ex vivo with anti-FasL expanded to higher levels in vivo, acquired a less exhausted phenotype, and more effectively treated established B16 melanoma tumors compared to controls. Similarly, T cells expanded with anti-FasL and genetically engineered with an anti-CD19 chimeric antigen receptor exhibited reduced differentiation and augmented anti-lymphoma and anti-leukemia activity compared to controls.
These studies demonstrate that blockade of Fas-mediated death and differentiation can preserve the younger qualities desired in T cells grown for adoptive cell therapy for cancer.
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