The current treatment strategies in advanced malignancies remain limited. Notably, immunotherapies have raised hope for a successful control of these advanced diseases, but their therapeutic responses are suboptimal and vary considerably among individuals. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME. Furthermore, targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies. In this review, we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition, tumor vaccines and adoptive cell transfer therapies, and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.

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Targeting tumor-associated macrophages to synergize tumor immunotherapy.

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1 Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses Our data identify a unique role for DCs in the PD-L1–PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells Mellman and colleagues show that dendritic cells represent a key source of PD-L1 in the tumor microenvironment, thereby restricting tumor infiltration by CD8+ T cells and antitumor responses

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer

Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that "deviate" from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.

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Interpretation of T cell states from single-cell transcriptomics data using reference atlases.

Tumor-associated macrophages (TAMs) can be educated within the tumor microenvironment to promote cancer development and progression. While TAM-targeted agents have largely focused on macrophage depletion as an anticancer strategy, it is becoming increasingly evident that TAM re-education may represent a more effective approach. In this perspective, we discuss different means to achieve TAM re-education, and review the beneficial effects of these strategies, particularly when combined with immune checkpoint inhibitors.

https://serval.unil.ch/resource/serval:BIB_7E2B9DDA760A.P001/REF.pdf

Re-education of macrophages as a therapeutic strategy in cancer.

Immune-checkpoint blockades (ICBs) have been routinely implemented to treat metastatic urothelial cancer (mUC), whereas robust biomarkers are urgently warranted. Herein, we explored latent promising biomarkers based on 348 pretreatment mUC samples from IMvigor210. Methods: The genome, transcriptome, immunome, and metabolome were systemically analyzed using the external TCGA dataset for validation. Kaplan-Meier and ROC curve analyses were performed to estimate the predictive capacity of M1-macrophage infiltration. Chi-square/Spearman/Mann Whitney U test are used to determine its correlation to genetic, biochemical, and clinicopathological parameters. Results: M1 frequency is a robust biomarker for predicting the prognosis and response to ICBs, which is non-inferior to tumor mutation burden (TMB) or tumor neoantigen burden (TNB), and exceeds CD8 T cells, T cell inflamed gene expression profile (GEP), and PD-L1 expression. Moreover, M1 infiltration is associated with immune phenotypes (AUC = 0.785) and is negatively correlated with immune exclusion. Additionally, transcriptomic analysis showed immune activation in the high-M1 subgroup, whereas it showed steroid and drug metabolism reprograming in the M1-deficient subset, which characterized the limited sensitivity to ICB therapy. Notably, investigation of the corresponding intrinsic genomic profiles highlighted the significance of TP53 and FGFR alterations. Conclusions: M1 infiltration is a robust biomarker for immunotherapeutic response and immunophenotype determination in an mUC setting. Innate immunity activation involving macrophage polarization remodeling and anti-FGFR mutations may be promising strategies for synergy with anti-PD-L1 treatments and may help prolong the clinical survival of patients with mUC.

Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer.

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 IFNγ and was associated with enhanced T-cell activity. Transfer of monocytes into anti-PD-L1-treated 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 IFNγ 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. SIGNIFICANCE: This work demonstrates that increased IFNγ signaling following anti-PD-L1 treatment can remodel the macrophage compartment to enhance T-cell responses.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1493/F1.large.jpg.

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

Exhausted T cells have been described in cancer patients and murine tumor models largely based on their expression of various inhibitory receptors. Understanding of the functional attributes of these cells is limited. Here, we report that among CD8+ T cells in commonly used syngeneic tumor models, the coexpression of inhibitory receptors PD-1, LAG3, and TIM3 defined a group of highly activated and functional effector cells. Coexpression of these receptors further enriched for antigen-specific cells with increased T-cell receptor clonality. Anti-PD-L1 treatment increased the number and activation of these triple-positive CD8+ T cells without affecting the density of PD-1- cells. The intratumoral density of CD8+ T cells coexpressing inhibitory receptors negatively correlated with tumor burden. The density ratio and pretreatment phenotype of CD8+ T cells coexpressing inhibitory receptors was positively correlated with response across a variety of tumor models. Our results demonstrate that coexpression of inhibitory receptors is not a signifier of exhausted T cells, but rather can define a group of activated and functional effector cells in syngeneic tumor models. In the cancer setting, these cells could represent a heterogeneous population of not only exhausted but also highly activated cells responsive to treatment.

https://cancerimmunolres.aacrjournals.org/content/canimm/7/6/963.full.pdf

Coexpression of Inhibitory Receptors Enriches for Activated and Functional CD8+ T Cells in Murine Syngeneic Tumor Models

Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy. Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment. Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

https://jitc.bmj.com/content/jitc/8/2/e001439.full.pdf

Ryan Rodriguez

Papers

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

Coexpression of Inhibitory Receptors Enriches for Activated and Functional CD8+ T Cells in Murine Syngeneic Tumor Models

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy