Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors

Abstract

Tumor indoleamine 2,3-dioxygenase (IDO) promotes immunosuppression by direct action on effector T cells and Tregs and through recruitment, expansion and activation of myeloid-derived suppressor cells (MDSCs). Targeting of MDSCs is clinically being explored as a therapeutic strategy, though optimal targeting strategies and biomarkers predictive of response are presently unknown. Maturation and tumor recruitment of MDSCs are dependent on signaling through the receptor tyrosine kinase CSF-1R on myeloid cells. Here, we show that MDSCs are the critical cell population in IDO-expressing B16 tumors in mediating accelerated tumor outgrowth and resistance to immunotherapy. Using a clinically relevant drug, we show that inhibition of CSF-1R signaling can functionally block tumor-infiltrating MDSCs and enhance anti-tumor T cell responses. Furthermore, inhibition of CSF-1R sensitizes IDO-expressing tumors to immunotherapy with T cell checkpoint blockade, and combination of CSF-1R blockade with IDO inhibitors potently elicits tumor regression. These findings provide evidence for a critical and functional role for MDSCs on the in vivo outcome of IDO-expressing tumors.

FcγR interaction is not required for effective anti‐PD‐L1 immunotherapy but can add additional benefit depending on the tumor model

“…We observed that this enhanced antitumor efficacy correlated with the reduction of a tumor‐infiltrated myeloid subset in CT26 tumor. For this tumor model, an association between an elevated number of myeloid cells and the increased magnitude of their immunosuppressive tumor microenvironment was reported while elimination of these cells can lead to strong antitumor responses . Preferential reduction of this myeloid subset by anti‐PD‐L1 mIgG2a may be due to its high levels of surface PD‐L1 expression compared to other immune and nonimmune cells, similar to that proposed for anti‐CTLA4 mAb, which preferentially depletes high CTLA4 expressing regulatory T cells .…”

Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade

“…Others have also reported the surprising ability of very few T cells to mount a potent immune response in KPC tumours (Evans et al , ). In general, increased T‐cell numbers follow CSF‐1(R) blockade in a variety of tumour models, but rarely results in growth inhibition without additional therapies (Strachan et al , ; Mok et al , ; Zhu et al , ; Holmgaard et al , ; Seifert et al , ). For example, Zhu et al () found that combining CSF‐1R blockade with anti‐CTLA4 or PD‐L1 resulted in significant growth inhibition in orthotopic pancreatic tumours.…”

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…Thus, IDO1 exerted regulatory control over MDSC suppressive function by its ability to influence the inflammatory milieu. Other studies show that IDO1 is needed for MDSC recruitment to tumors (Holmgaard et al , 2016; Holmgaard et al , 2015). In light of the pivotal role of IDO1 in supporting MDSC function, it is notable that no compelling evidence exists in mouse models that IDO1 is expressed directly in MDSC.…”