Polyamine Blocking Therapy Decreases Survival of Tumor-Infiltrating Immunosuppressive Myeloid Cells and Enhances the Antitumor Efficacy of PD-1 Blockade

Abstract

◥Despite unprecedented advances in the treatment of cancer through the use of immune checkpoint blockade (ICB), responses are not universal and alternative strategies are needed to enhance responses to ICB. We have shown previously that a novel polyamine blocking therapy (PBT), consisting of cotreatment with a-difluoromethylornithine (DFMO) to block polyamine biosynthesis and a Trimer polyamine transport inhibitor, decreases myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM). Both MDSCs and TAMs promote tumor progression, inhibit antitumor immunity, and limit the efficacy of ICB. In this study, we investigated the use of PBT to heighten therapeutic responses to PD-1 blockade in mice bearing 4T1 mammary carcinoma and B16F10 melanoma tumors. Whereas PBT inhibited primary tumor growth in both tumor models, 4T1 lung metastases were also dramatically decreased in mice treated with PBT. Reduc-tions in MDSC and TAM subpopulations in 4T1 tumors from PBTtreated mice were accompanied by reduced cytoprotective autophagy only in tumor-infiltrating MDSC and macrophage subpopulations but not in the lung or spleen. PBT treatment blunted M2-like alternative activation of bone marrow-derived macrophages and reduced STAT3 activation in MDSC cultures while increasing the differentiation of CD80 þ , CD11c þ macrophages. PBT significantly enhanced the antitumor efficacy of PD-1 blockade in both 4T1 and B16F10 tumors resistant to anti-PD-1 monotherapy, increasing tumor-specific cytotoxic T cells and survival of tumor-bearing animals beyond that with PBT or PD-1 blockade alone. Our results suggest that cotreatment with DFMO and the Trimer polyamine transport inhibitor may improve the therapeutic efficacy of immunotherapies in patients with cancer with resistant tumors.

Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity

“…These results are consistent with the results of our recent study where polyamine blockade promoted CD8 + T-cell infiltration and worked in concert with anti-PD1 or anti-PDL1 immunotherapy to further promote animal survival in mouse models of glioblastoma [ 73 ]. The combinatorial effect of polyamine blockade and checkpoint immunotherapy was also demonstrated in mouse models of mammary carcinogenesis [ 76 ]. The results of these studies clearly demonstrate that polyamine blockade can alter the TME to promote immune functionality.…”

Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment

“…PBT-associated anti-tumor immune response has been tested in colon carcinoma and melanoma preclinical studies [ 15 , 20 ]. Studies have also shown the success of combining PBT with anti-PD-L1 therapy in mammary carcinoma and melanoma xenograft models [ 22 ]. Furthermore, preclinical studies from our group using PBT showed increased survival of pancreatic tumor-bearing mice [ 10 ].…”

Targeting Myeloid-Derived Suppressor Cells to Enhance the Antitumor Efficacy of Immune Checkpoint Blockade Therapy

“…Polyamine blocking therapy (PBT) can redirect the differentiation of MDSCs to pro-inflammatory M1-like macrophages through the downregulated expression of p-STAT3, an oncogenic transcription factor whose activation is implicated in MDSCs differentiation and survival. PBT significantly enhanced the antitumor efficacy of PD-1 blockade in both 4T1 mammary carcinoma and B16F10 melanoma tumors resistant to anti-PD-1 monotherapy, increasing tumor-specific cytotoxic T cells and survival of tumor-bearing animals beyond that with PBT or PD-1 blockade alone ( 99 ). Several studies indicate that all-trans retinoic acid (ATRA) is another agent that can promote myeloid cells maturation and reduce the number of MDSCs in the TME.…”