BackgroundVSIG4 (V-set immunoglobulin-domain-containing 4) is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance as well as a negative regulator of T cell activation by an undetermined mechanism.1–3 VSIG4 is expressed in tumor associated macrophages (TAMs) with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, and glioma, suggesting an important role in tumor immune evasion.3–6 Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing TAMs to an inflammatory phenotype capable of coordinating an anti-tumor immune response.MethodsThe ability of anti-VSIG4 antibodies to repolarize M2-like macrophages and induce T cell activation was assessed in vitro and ex vivo, by measuring production of inflammatory mediators. In vitro assays were performed primarily with M-CSF plus IL-10 driven monocyte-derived M2c macrophages from healthy donors. Ex vivo assays were performed with fresh, patient-derived tumor samples in culture. To determine whether targeting VSIG4 can lead to an anti-tumor effect in vivo, syngeneic mouse models were dosed with anti-mouse VSIG4 antibodies and characterized for changes in tumor volume and immune cell populations.ResultsIn in vitro and ex vivo assays anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Targeting VSIG4 upregulates pro-inflammatory cytokines in M2c macrophages, as well as upregulates pro-inflammatory myeloid-derived cytokines and T cell-derived cytokines in M2c macrophages co-cultured with autologous T cells in the presence of staphylococcal enterotoxin B (SEB) activation. To assess targeting VSIG4 in a relevant translational model, fresh, patient-derived tumor samples were treated ex vivo with anti-VSIG4. Across multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels greater than observed by treatment with anti-PD-1 or a clinical macrophage repolarizing agent (anti-ILT-4). In vivo, tumor growth inhibition is observed in syngeneic mouse models dosed with anti-mouse-VSIG4 alone and in combination with anti-PD-1.ConclusionsTaken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms.Referencesvan Lookeren Campagne M, Verschoor A. Pathogen clearance and immune adherence “revisited”: immuno-regulatory roles for CRIg. Semin Immunol 2018;37:4–11.Xu S, Sun Z, Li L, Liu J, He J, Song D, Shan G, Liu H, Wu X. Induction of T cells suppression by dendritic cells transfected with VSIG4 recombinant adenovirus. Immunol Lett 2010;128(1):46–50.Liao Y, Guo S, Chen Y, Cao D, Xu H, Yang C, Fei L, Ni B, Ruan Z. VSIG4 expression on macrophages facilitates lung cancer development. Lab Invest 2014;94(7):706–715.Roh J, Jeon Y, Lee A, Lee S, Kim Y, Sung C, Park C, Hong J, Yoon D, Suh C, Huh J, Choi I, Park C. The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma. Oncotarget 2017;8(35):58122–58132.Xu T, Jiang Y, Yan Y, Wang H, Lu C, Xu H, Li W, Fu D, Lu Y, Chen J. VSIG4 is highly expressed and correlated with poor prognosis of high-grade glioma patients. Am J Transl Res 2015;7(6):1172–1180.Byun J, Jeong D, Choi I, Lee D, Kang M, Jung K, Jeon Y, Kim Y, Jung E, Lee K, Sung M, Kim K. The significance of VSIG4 expression in ovarian cancer. Int J Gynecol Cancer 2017;27(5):872–878.Ethics ApprovalAll legal and ethical requirements were met with regards to the humane treatment of animals described in the study. The animal study was conducted in compliance with CRL IACUC under IACUC No. I033.
e15090 Background: Macrophages are both antigen presenting and effector cells of the innate immune system and play an important role in tissue homeostasis as well as in activation and modulation of the adaptive immune response in disease. They display phenotypic heterogeneity in different tissue environments but can be broadly subdivided into pro-inflammatory M1 macrophages, which promote immune response, and anti-inflammatory M2 macrophages, which are associated with immune suppression. Under steady-state conditions, the populations of immune-stimulatory and immune-regulatory macrophages are balanced, but disruption of this balance can result in disease. In the tumor microenvironment, tumor-associated macrophages (TAMs) acquire an M2-like phenotype and maintain suppression of the immune system and promotion of tumor progression. Methods: For functional screening of anti-PSGL-1 antibodies, monocytes were isolated from peripheral blood mononuclear cells (PBMC) obtained from healthy donors and differentiated into M2 macrophages in the presence or absence of anti-PSGL-1 antibodies. On day 8 of the assay, phenotypic profile of cells was analyzed by flow cytometry and chemokines / cytokines were measured by Luminex. Mixed-lymphocyte reaction assay, SEB assay and an ex vivo tumor model were used to further assess antibody functionality in a multi-cellular assay format. For T cell assays, purified T cells from PBMC were stimulated in the presence or absence of anti-PSGL-1 antibodies and responses were characterized by flow cytometry and Luminex. Results: We have identified PSGL-1 as a novel macrophage checkpoint. Our work demonstrates that targeting PSGL-1 via an antagonistic antibody re-polarizes human primary M2 macrophages to a more M1-like state both phenotypically and functionally. We observe this M2-to-M1 switch to have an impact on immune cell communication in complex multi-cellular assays. Moreover, targeting of PSGL-1 in an ex vivo tumor system demonstrates that anti-PSGL-1 treatment can increase pro-inflammatory cytokine and chemokine production known to be associated with beneficial clinical response. These effects can be predominantly attributed to macrophage modulation, as antibody targeting PSGL-1 on purified T cells has a very small, if any, impact on their activation and effector function. Conclusions: Our results demonstrate that treatments inducing macrophage phenotypic switches can promote an immune response in a tumor setting across multiple tumor types and provide support for targeting the novel macrophage checkpoint PSGL-1 across multiple cancer indications.
BackgroundSuppressive myeloid cell populations in the tumor microenvironment (TME) are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical trials have produced positive data for therapies aimed at repolarizing immuno-suppressive myeloid populations in the TME. One new macrophage repolarizing target, PSGL-1 (P-selectin glycoprotein ligand-1), is expressed at high levels on suppressive tumor-associated macrophages (TAMs) and in vitro differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining an immuno-suppressive macrophage state.MethodsTo assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model.ResultsWe have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-alpha/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays.Pre-clinical efficacy of the anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment.Lastly, our lead anti-PSGL-1 antibody also showed in vivo anti-tumor effect in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood.ConclusionsThe data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer.Ethics ApprovalAll legal and ethical requirements were met with regards to the humane treatment of animals described in the study. The animal study was conducted in compliance with IACUC PROTO202000042 and the institutional assurance certification of the University of Massachusetts Medical School. The University of Massachusetts Medical School is fully accredited by AAALAC and has an Animal Welfare Assurance on file with the Office of Laboratory Animal Welfare (OLAW).
Suppressive myeloid cells in the tumor microenvironment (TME) are associated with poor survival of cancer patients and resistance to T cell checkpoint inhibitors. These myeloid cells shield cancer cells from the sentinel immune response and create a niche for tumor growth. Repolarizing immuno-suppressive myeloid populations in the TME attracted considerable interest from scientific community and several companies, and has produced early positive clinical data. One of the targets that potently sustains macrophage suppressive phenotypes and is highly expressed on tumor associated macrophages is PSGL-1. Blocking a previously unknown epitope on PSGL-1 triggers macrophage repolarization to a pro inflammatory state. We have determined that our therapeutic candidate VTX-0811, anti-PSGL-1 monoclonal antibody (mAb), repolarizes M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed by primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that VTX-0811 upregulated TNF-α/NF-κB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism, and Myc signaling pathways, consistent with a broad M2-to-M1 shift. Furthermore, repolarized macrophages enhanced inflammatory responses in complex primary multi-cellular assays.VTX-0811 also showed efficacy in a humanized mouse PDX model of melanoma. VTX-0811 suppressed tumor growth to a significantly greater degree compared with an anti-PD-1 mAb. At the cellular and molecular levels, the treatment led to an inflammatory microenvironment, including a reduced MDSC population, and increased systemic pro-inflammatory mediators. Compared with anti-PD-1 monotherapy, VTX-0811 alone and in combination with anti-PD-1 increased the fraction of CD8+ T cells among the infiltrating T cells. Significant combination effects of VTX-0811 plus anti-PD-1 were seen within the tumor tissue, spleen, and peripheral blood.Additionally, pre-clinical efficacy of VTX-0811 was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve cellular and molecular composition of the TME. VTX-0811 increased secretion of inflammatory cytokines and chemokines known to be involved in immune activation of the TME and fresh leukocyte recruitment, as well as linked to clinical response to T cell checkpoint inhibitors.VTX-0811 is a humanized high affinity IgG4/κ mAb that demonstrated safety in NHP primates up to 200mg/kg dosed weekly for 5 total doses. VTX-0811 does not induce activation of unstimulated PBMC or unstimulated blood-derived neutrophil or T cell cultures. These data provide biological and mechanistic support for advancing this program into the clinic with a first in human trial planned for early 2022. Citation Format: Igor Feldman, Tatiana Novobrantseva, Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Susan Low, Steve Sazinsky, Michael Brehm, Boris Klebanov. VTX-0811, a first-in-class PSGL-1 blocking monoclonal antibody, repolarizes tumor associated macrophages and induces inflammation in the tumor microenvironment, leading to suppression of tumor growth in pre-clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5602.
BackgroundMacrophages play an important role in cancer by modulating both the innate and adaptive parts of the immune system. In non-pathological conditions, multiple subsets of macrophages balance the immune response. In cancer, M2-like immune-suppressive tumor-associated macrophages (TAMs) dominate the tumor microenvironment (TME). TAMs promote tumor growth, support neo-angiogenesis and enable metastasis formation. Macrophage modulators driving macrophage repolarization from the M2-like to a pro-inflammatory M1-like phenotype are an attractive novel class of cancer immunotherapy. Here we present identification, validation, and pre-clinical data of a novel macrophage checkpoint, PSGL-1, which supports targeting this molecule for immune-oncology.MethodsTo assess the therapeutic potential of using anti-PSGL-1 antibodies to convert macrophage phenotype and the tumor microenvironment toward a more inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model.ResultsWithin the multiple subsets of macrophages, PSGL-1 is expressed at high levels on immune-suppressive TAMs and in vitro differentiated M2 macrophages. We show that targeting PSGL-1 via an antagonistic antibody repolarized M2 macrophages to a more M1-like state, both phenotypically and functionally as assessed in primary in vitro macrophage assays. Further, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays, including SEB stimulated PBMC assays and mixed-lymphocyte reactions (MLRs).To establish a pre-clinical proof-of-concept for targeting PSGL-1, we turned to ex vivo cultures of fresh patient-derived primary tumors, where the complexity of the TME can be most preserved. RNA-seq data show that ex vivo cultures treated with anti-PD-1 antibody recapitulate TME changes in anti-PD-1 treated patients, including a strong T-cell IFN-gamma signature and a reduction in oncogenic pathway activation. Blocking PSGL-1 resulted in a robust pro-inflammatory signature driven by TNF-alpha/NF-kappa-B and chemokine-mediated signaling. The increase in TNF-alpha signaling was accompanied by reduction in oxidative phosphorylation and fatty acid metabolism. The increase in pro-inflammatory cytokine and chemokine production was confirmed by measuring secreted protein levels, further confirming the re-polarization of macrophages within a tumor setting.Lastly, we employed a humanized mouse PDX model of melanoma and show that anti-PSGL-1 treatment resulted in suppression of tumor growth favorably compared to anti-PD-1. At the cellular and molecular levels, anti-PSGL-1 treatment lead to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, increased antigen presentation, pro-inflammatory mediators, and effector T cell infiltration and activation.ConclusionsOur data support anti-PSGL-1 as a macrophage repolarizing agent and an effective macrophage-targeted therapy for Immuno-Oncology.
Our Translational Science Platform uses an unbiased bioinformatics-based approach to interrogate particular cell types within the tumor microenvironment (TME). Given the correlation between high levels of immune-suppressive macrophages within the tumor TME and poor patient prognosis across a number of solid tumor types we focused initially on developing novel immunotherapies to modify this cell type. We identified 10 targets as candidates for converting tumor-associated macrophages from immune-suppressing to immune-enhancing. One of these targets was TIM3. To date, TIM3 has been pursued mainly as a checkpoint target for T cell-directed immunotherapies based on its expression on exhausted T cells. Anti-TIM3 mAbs, generated by multiple groups, induce responsiveness in T cells and demonstrate anti-tumor benefit in certain mouse models. However, our macrophage-centric approach has identified a previously unrecognized protein-protein interaction between TIM3 and one of our additional macrophage targets. Based on knowledge of this interaction, we were able to generate and select for panels of mAbs to TIM3 and to its binding partner capable of converting macrophages from an “M2” to an “M1” pro-inflammatory phenotype. In contrast to published anti-TIM3 mAbs, our particular anti-TIM3 mAbs lacked activity in T cell-based assays, but promoted an increase in pro-inflammatory cytokines with a reduction or no effect in anti-inflammatory cytokines in a macrophage activity assay. In this assay, monocytes were prepared from human peripheral blood and cultured in the presence of M-CSF to bias toward an M2 phenotype. Under sub-optimal stimulation with LPS or CD40L or HMGB1, treatment of these cells with the anti-TIM3 mAbs led to increases in pro-inflammatory cytokines including IL-1β and TNFα. The conversion to an “M1” macrophage by anti-TIM3 mAbs had downstream consequences on T cells as demonstrated by mixed lymphocyte reaction experiments. In these studies, the addition of anti-TIM3 led to a macrophage-dependent increase in IFNγ from the T cells. To assess the impact of our anti-TIM3 mAbs in the tumor setting, tumor histoculture experiments were performed. Tumor tissue slices from ovarian cancer patients treated with anti-TIM3 showed an increase in a range of cytokines and in this tumor setting the initial sub-optimal stimulus was not required. Specific antibodies to TIM3 and its binding partner that are able to promote a pro-inflammatory macrophage phenotype have been generated. We are developing these as modulators of the TME, to be assessed either as single agents or in combination with other therapies such as checkpoint inhibitors. Citation Format: Jamie Wong, Ryan Phennicie, Igor Feldman, Sriram Sathyanarayanan, Don Shaffer, Mohammad Zafari, Steve Sazinsky, Kenneth Crook, Debbie Law. Discovery of a novel TIM3 binding partner and a key role for TIM3 on macrophages: Identification of specific antibodies capable of converting immune-suppressive macrophages to immune-enhancing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 586.
VSIG4 (V-set immunoglobulin-domain-containing 4) is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance, via interactions with C3 fragments, as well as a negative regulator of T cell activation by an undetermined mechanism. VSIG4 is expressed in tumor associated macrophages with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, stomach cancer and glioma, suggesting an important role in tumor immune evasion. Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing tumor associated macrophages (TAMs) to an inflammatory phenotype capable of coordinating an anti-tumor immune response. Through a series of in vitro and ex vivo assays we demonstrate that anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Anti-VSIG4 antibodies upregulate pro-inflammatory cytokines in M-CSF plus IL-10 driven monocyte-derived M2c macrophages, as well as in TAM-like macrophages in vitro derived from monocytes cultured in the presence of ascites fluid from ovarian cancer patients. To determine whether anti-VSIG4-induced macrophage repolarization can activate T cells, monocyte-derived M2c macrophages were co-cultured with autologous T cells in the presence of staphylococcal enterotoxin B (SEB) activation and anti-VSIG4 antibodies. Here, anti-VSIG4 antibodies upregulate both pro-inflammatory myeloid-derived cytokines (GM-CSF) and T cell-derived cytokines (IFNγ). To extend these observations to a relevant translational model, we treated fresh, patient-derived tumor samples with anti-VSIG4 antibodies and relevant controls ex vivo. Across numerous patient-derived samples, which included multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels greater than observed by treatment with anti-PD-1 or a clinical macrophage repolarizing agent (anti-ILT-4). Taken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms. Citation Format: Steve Sazinsky, Ani Nguyen, Mohammad Zafari, Ryan Phennicie, Joe Wahle, Veronica Komoroski, Kathryn Rooney, Craig Mizzoni, Boris Klebanov, Jessica Ritter, Denise Manfra, Igor Feldman, Tatiana Novobrantseva. Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P105.
Suppressive myeloid populations in the tumor microenvironment are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical studies have produced positive data for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. One new macrophage repolarizing target, PSGL-1, is expressed at high levels on immuno-suppressive TAMs and differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining a suppressive functional macrophage state. To assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model. We have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-a/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays. The PSGL-1 antibody also showed efficacy in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood. Lastly, pre-clinical efficacy of our lead anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment. The data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer. Citation Format: Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Veronica Komoroski, Brian O'Nuallain, Ryan Phennicie, Kevin Kauffman, Dominika Nowakowska, Joe Wahle, Steve Sazinsky, Michael Brehm, Igor Feldman, Tatiana Novobrantseva. PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P107.
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