Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer

Abstract

Myeloid-derived suppressor cells (MDSC) are one of the major factors limiting the efficacy of immune therapy. In a clinical trial of patients with extensive stage small cell lung cancer (SCLC) we tested the possibility that targeting MDSC can improve the induction of immune responses by a cancer vaccine. Forty-one patients with extensive stage SCLC were randomized into three arms: arm A - control, arm B - vaccination with dendritic cells transduced with wild-type p53, and arm C – vaccination in combination with MDSC targeted therapy with all-trans retinoic acid (ATRA). Interim results of the ongoing clinical trial are presented. Pre-treatment levels of MDSC populations in patients from all three arms were similar. Vaccine alone did not affect the proportion of MDSC, whereas in patients treated with ATRA the MDSC decreased more than two-fold (p=0.02). Before the start of treatment no patients had detectable p53 specific responses in IFN-γ ELISPOT. Sequential measurements did not show positive p53 responses in any of the 14 patients from arm A. After immunization, only 3 out of 15 patients (20%) from arm B developed a p53-specific response (p=0.22). In contrast, in arm C 5 out of 12 patients (41.7%) had detectable p53 responses (p=0.012). The proportion of granzyme B positive CD8+ T cells was increased only in patients from arm C but not in arm B. Depletion of MDSC substantially improved the immune response to vaccination suggesting that this approach can be used to enhance the effect of immune interventions in cancer.

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

“…20,33 Importantly, numerous studies in mice have shown that the depletion of MDSC or interference with their immunosuppressive activity improves antitumor response and delays tumor growth. 20,21,[34][35][36] Nevertheless, although several compounds have been shown to decrease MDSC frequencies in the peripheral blood and to restore T cell functions measured ex vivo, 37,38 only marginal clinical benefit if any has been observed.…”

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…ATRA exerts a direct effect on MDSCs by inducing PMN-MDSC apoptosis and differentiating M-MDSCs to Ms and DCs. 106 Indeed, a number of clinical pharmacological agents currently in use (e.g., PDE5 inhibitors, COX-2 inhibitors, ARG1 inhibitors, bisphosphonates, gemcitabine, and paclitaxel) and other agents currently in preclinical testing may play a fundamental role in promoting anti-tumor immune responses by inhibiting MDSC functionality. 11 …”

Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease

“…Importantly, MDSC granulocytic function was also reduced based on the production of arginase-1. Iclozan et al (2013) evaluated patients (48-74 years old) with small-cell lung cancer who received a standard platinum/etoposide regimen and 4-6 weeks later were vaccinated with dendritic cells (DCs) or DC and alltrans retinoic acid (ATRA) therapy which has been shown to reduce MDSCs (Nefedova et al 2007). Vaccine + ATRA decreased MDSC numbers, led to a higher number of patients with detectable p53 responses and increased the frequency of granzyme B + CD8 + T cells (Iclozan et al 2013).…”