Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ

Abstract

Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T cell-inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte-dependent primary tumor growth delay and prolonged survival only in T cell-inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity f tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low dose use of isoform-specific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade.

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

“…A prior study with murine and human data showed that chemotherapy (carboplatin and paclitaxel) reduces numbers of immunosuppressive MDSCs in cervical cancer (41). Although the MOC1 model is largely driven by MDSCs (28), we did not see any differences in MDSC numbers in tumors from cisplatin-treated mice in our study, though we did not look at multiple time points or perform functional studies.…”

“…We explored this possibility in mice bearing MOC1 tumors, which typically induce immune responses and respond to immunotherapies, whereas MOC2 tumors, which are aggressive, do not typically induce immune responses and do not respond well to immunotherapies (16, 17, 22, 28). In MOC1-bearing mice, cisplatin (5 mg/kg/week) and anti–PD-L1 did not delay tumor growth when used alone but provided a significant tumor growth delay and prolonged survival when used concurrently (Fig.…”

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

“…The therapeutic effects of the combination therapy were further validated in the Murine oral cancer 1 (MOC1) model that is generated from 7,12-dimethylbenz[a]anthracene-induced (DMBA-induced) murine primary oral cavity squamous cell carcinoma (45). MOC1 cells form T cell-inflamed tumors capable of inducing immunologic memory (46). The combined TLR7/9 plus anti-PD-1 therapy was as effective in the MOC1 model as other HNSCC models (Supplemental Figure 2).…”

Oncogenic KRAS Drives Immune Suppression in Colorectal Cancer

“…Increased CXCL3 expression in Kras mutant tumors leads to recruitment of CXCR2 + PMN-MDSCs, which in turn suppress infiltration by CD4 + and CD8 + T cells, thus generating anti-PD-1 refractory tumors. PMN-MDSCs are observed in human CRC (Condamine et al, 2016) and appear to regulate response to immune checkpoint blockade in other cancers (Davis et al, 2017;Weber and Fottner, 2018) With the success of immunotherapy, the fields of cancer biology and cancer immunology are finally becoming integrated, and the impact of proto-oncogene and tumor suppressor mutations on the microenvironment and immune response is now being elucidated (Wellenstein and de Visser, 2018). Oncogenic KRAS has been found to promote MDSC recruitment via induced expression of granulocyte-macrophage colony stimulating factor (GM-CSF) and CXCL1/2 in murine pancreatic and lung cancer, respectively, and to even promote PD-L1 expression in lung cancer (Wellenstein and de Visser, 2018).…”