Immunosuppressive myeloid cells blockade in the glioma microenvironment enhances the efficacy of immune stimulatory gene therapy

NEHA KAMRAN; MARIANELA CANDOLFI; N RAJA; MARIA G CASTRO; VANDANA SAXENA; MARIELA MORENO AYALA; PEDRO R LOWENSTEIN; P KADIVALA; Y LI; D SHAH

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2017 vol. 25 p. 232 - 238

1525-0016

Survival of glioma (GBM) patients treated with the currentstandard of care remains dismal. Immunotherapeutic approachesthat harness the cytotoxic and memory potential ofthe host immune system have shown great benefit in othercancers. GBMs have developed multiple strategies, includingthe accumulation of myeloid-derived suppressor cells (MDSCs)to induce immunosuppression. It is therefore imperative todevelop multipronged approaches when aiming to generate arobust anti-tumor immune response. Herein, we testedwhether combining MDSC depletion or checkpoint blockadewould augment the efficacy of immune-stimulatory herpes simplextype-I thymidine kinase (TK) plus Fms-like tyrosine kinaseligand (Flt3L)-mediated immune stimulatory gene therapy.Our results show that MDSCs constitute >40% of the tumorinfiltratingimmune cells. These cells express IL-4Ra, induciblenitric oxide synthase (iNOS), arginase, programmed deathligand 1 (PDL1), and CD80, molecules that are criticallyinvolved in antigen-specific T cell suppression. Depletion ofMDSCs strongly enhanced the TK/Flt3L gene therapy-inducedtumor-specific CD8 T cell response, which lead to increasedmedian survival and percentage of long-term survivors. Also,combining PDL1 or CTLA-4 immune checkpoint blockadegreatly improved the efficacy of TK/Flt3L gene therapy. Ourresults, therefore, indicate that blocking MDSC-mediatedimmunosuppression holds great promise for increasing theefficacy of gene therapy-mediated immunotherapies for GBM.