Enhancement of Antitumor Immunity in Lung Cancer by Targeting Myeloid-Derived Suppressor Cell Pathways

Abstract

Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of frontline therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term anti-tumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective anti-tumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8+ T cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8+ T cell response and further decreased T regulatory cell infiltration. For long-term anti-tumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively-transferred memory cells responded to tumor re-challenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, generate effector and persistent memory cells for tumor eradication, and prevent lung cancer relapse.

The Stress-Response Sensor Chop Regulates the Function and Accumulation of Myeloid-Derived Suppressor Cells in Tumors

“…Although there are no current therapies to block Chop, some therapeutic possibilities could include the inhibition or scavenging of ROS and/or PNT (Bronte et al, 2005; Corzo et al, 2009; De et al, 2005; Lu et al, 2011; Sawant et al, 2013). Indeed, treatment with L-NAC reduced tumor growth and blocked Chop expression in MDSCs.…”

The emerging role of myeloid-derived suppressor cells in lung diseases

“…SRIVASTAVA et al [93] demonstrated that Snail, an activating transcription factor in epithelial-mesenchymal transition, induces tumour growth and metastasis by increasing MDSCs via increasing intracellular expression of ARG1 in murine lung tumour microenvironment. In other murine models of lung cancer, targeting of MDSCs using antibodies improved antitumor activity via enhancing effector and memory T-cell responses, as well as NK cell and antigen-presenting cell activities [94][95][96]. Peripheral blood MDSCs levels were shown to correlate with a higher tumour burden and a worse prognosis [97][98][99].…”

The Non–Small Cell Lung Cancer Immune Contexture. A Major Determinant of Tumor Characteristics and Patient Outcome

“…This comparative analysis of metastases from colorectal and renal cell cancers within the same organ, the lung, in relation to the primary site suggested that the malignant cell rather that the host tissue influences the establishment of a specific immune contexture driving clinical outcome. 1 T-cell responses, as well as natural killer (NK) cell and antigen-presenting cell activity (47).…”