Anti–PD-L1 Treatment Results in Functional Remodeling of the Macrophage Compartment

Abstract

© 2019 American Association for Cancer Research T cells T cells aPDL1 MHCI and MHCII ARGI iNOS CD40 CD86 proinflammatory cytokines Phagocytosis pathways Proinflammatory Suppressive MacrophageWithout treatment, tumor macrophages maintain a suppressive phenotype.Following anti-PD-L1 treatment, increased IFN signaling remodels the macrophage compartment towards a more proinflammatory phenotype, which can enhance T-cell responses.Remodeling of the macrophage compartment is driven by IFN following anti-PD-L1 treatment. Macrophage Cancer cells ARGI IFNγIFNγ Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid cells remains largely unknown. Here, we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment toward a more proinflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a proinflammatory, immunostimulatory phenotype. This polarization was driven mainly through IFNg and was associated with enhanced T-cell activity. Transfer of monocytes into anti-PD-L1treated tumor-bearing mice led to macrophage differentiation into a more proinflammatory phenotype, with an increase in CD8 T cells expressing granzyme-B and an increase in the CD8/Treg ratio compared with control-treated mice. Although in responsive tumor models, anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models toward a more proinflammatory phenotype, mainly through increased IFNg levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments.

Transfer learning between preclinical models and human tumors identifies conserved NK cell activation signature in anti-CTLA-4 responsive tumors

“…In contrast, pattern 12 in anti-PD-1 treated cells was enriched for M1 macrophage polarization and interferon responses (p < 1 x 10 -2 , Supplemental Table 1). This finding agrees with a recent study, which showed that anti-PD-1 treatment leads to a functional transition within the macrophage compartment towards an immunostimulatory M1 phenotype (Xiong et al, 2019).…”

Prognostic Impact of Tumor-Associated Macrophages on Survival Is Checkpoint Dependent in Classical Hodgkin Lymphoma

“…Given the accentuated expression of PD-L1 and IDO-1 in TAMs, high proportions of PD-L1 + TAMs and IDO-1 + TAMs also translated to inferior outcome. These survival associations were seen within both overall CD68 + TAMs and in CD163 + putative M2-like TAMs, suggesting subtype-independent association, although M2-like alternatively activated macrophages have been considered to be pro-tumoral [3] and promote immunosuppression [22]. On the contrary, in our study population, neither the proportion of macrophages (CD68 + or CD163 + ), nor the PD-L1 − or IDO-1 − TAMs translated to survival.…”

Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist

“…6 These therapies can also skew immunosuppressive cells like macrophages toward a more inflammatory, antitumor phenotype to support tumor rejection. 4 The effect of αPD-1/PD-L1 therapies on effector cell populations has recently undergone a paradigm shift with the demonstration that they do not primarily mediate their efficacy through reinvigoration of T cells in the TME. Instead, migration of novel, peripherally activated CD8 + T-cell clones is required for improved antitumor efficacy.…”

“…Recent studies have demonstrated that decreasing the number of immunosuppressive cells, systemic activation of effector immune cells and altered lymphocyte migration to the TME, not in situ expansion, mediate optimal antitumor responses. [2][3][4][5][6] The combination of immunotherapies that decrease immunosuppression and activate immune effector cells may improve antitumor efficacy and induce the aforementioned immune effects. Anti(α)-programmed cell death-1 (PD-1)/programmed cell deathligand 1 (PD-L1) antibodies decrease immune suppression by preventing the interaction of PD-L1 expressed on tumor or suppressive immune cells with PD-1 on natural killer (NK) and T cells.…”