http://manuscript.elsevier.com/S016836592200147X/pdf/S016836592200147X.pdf

Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.

Immune-checkpoint inhibitors have revolutionized cancer therapy, yet many patients either do not derive any benefit from treatment or develop a resistance to checkpoint inhibitors. Intrinsic resistance can result from neoantigen depletion, defective antigen presentation, PD-L1 downregulation, immune-checkpoint ligand upregulation, immunosuppression, and tumor cell phenotypic changes. On the other hand, extrinsic resistance involves acquired upregulation of inhibitory immune-checkpoints, leading to T-cell exhaustion. Current data suggest that PD-1, CTLA-4, and LAG-3 upregulation limits the efficacy of single-agent immune-checkpoint inhibitors. Ongoing clinical trials are investigating novel immune-checkpoint targets to avoid or overcome resistance. This review provides an in-depth analysis of the evolving landscape of potentially targetable immune-checkpoints in cancer. We highlight their biology, emphasizing the current understanding of resistance mechanisms and focusing on promising strategies that are under investigation. We also summarize current results and ongoing clinical trials in this crucial field that could once again revolutionize outcomes for cancer patients. 

Novel targets for immune-checkpoint inhibition in cancer.

Summary There is an increasing number of immune-checkpoint inhibitors being developed and approved for cancer immunotherapy. Most of the new therapies aim to reactivate tumour-infiltrating T cells, which are responsible for tumour killing. However, in many tumours, the most abundant infiltrating immune cells are macrophages and myeloid cells, which can be tumour-promoting as well as tumouricidal. CD200R was initially identified as a myeloid-restricted, inhibitory immune receptor, but was subsequently also found to be expressed within the lymphoid lineage. Using a mouse model humanised for CD200R and PD-1, we investigated the potential of a combination therapy comprising nivolumab, a clinically approved PD-1 blocking antibody, and OX108, a CD200R antagonist. We produced nivolumab as a murine IgG1 antibody and validated its binding activity in vitro as well as ex vivo. We then tested the combination therapy in the immunogenic colorectal cancer model MC38 as well as the PD-1 blockade-resistant lung cancer model LLC1, which is characterised by a large number of infiltrating myeloid cells, making it an attractive target for CD200R blockade. No significant improvement of overall survival was found in either model, compared to nivolumab mIgG1 monotherapy. There was a trend for more complete responses in the MC38 model, but investigation of the infiltrating immune cells failed to account for this. Importantly, MC38 cells expressed low levels of CD200, whereas LLC1 cells were CD200-negative. Further investigation of CD200R-blocking antibodies in tumours expressing high levels of CD200 could be warranted.

/pdf/combination-cd200r-pd-1-blockade-in-a-humanised-mouse-model-hb0remlo.pdf

Combination CD200R/PD-1 blockade in a humanised mouse model

The last several years have seen the introduction into clinical medicine of a family of reagents directed towards so-called “checkpoint inhibitors”, which act at gateways in a developing immune response to regulate unwanted and/or harmful self-directed activation responses. The molecules involved at such gateways generally belong to an extended immunoglobulin supergene family, and contribute inhibitory signals to dampen over-exuberant responses. They include, but are not limited to, molecules of the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand family; PD-1 and PDL-1; CD200 and CD200R; TIGIT and VISTA and their respective ligands (VSIG-3/IGSF11, Nectin), all of which are presumed to play a physiological role in maintaining natural self-tolerance. In the field of cancer immunotherapy, where the ultimate clinical goal is to improve immuno-targeting of cancer cells, triggering these checkpoint inhibitory signaling pathways, has the potential to thwart effective tumor immunity. This in turn has led to the characterization and application of multiple reagents, including antibodies and other designed inhibitory molecules, which can act as checkpoint blockade agents. Such reagents have had a dramatic effect on human cancer treatment, with marked success for anti-CTLA-4 and PD-1 in particular in clinical trials. This review elaborates on the promise on other more under-appreciated target molecules for checkpoint blockade in human B cell malignancies and solid tumors, particularly CD200:CD200R, and describes both the background, and newer studies, which highlight the potential importance of targeting the CD200:CD200R dyad in cancer immunobiology/therapy.

Updates on the Importance of CD200:CD200R Checkpoint Blockade in Solid Tumors and B cell Malignancies

Anti–PD-1/PD-L1 therapy, either by anti–PD-1 antibody or anti–PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti–PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti–PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen–specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic. Description The response to anti-PD-1/PD-L1 therapy involves CD200+ T cells, which both predict and mediate the beneficial response. Identifying responders A challenge for the field of cancer immunotherapy is identifying which patients will respond to immune checkpoint blockade treatments such as anti-PD-1 or anti-PD-L1. Here, Wang et al. showed using murine tumor models that CD200+ CD8+ T cells were crucial for the efficacy of anti-PD-1/PD-L1 therapy. These CD200+ cytotoxic T lymphocytes had a unique chromatin landscape and possessed superior anti-tumor effector functions as compared to CD200- CD8+ T cells. Further, the authors showed, using data from multiple patient cohorts, that CD200+ T cells could predict immunotherapy efficacy, suggesting that this cell population could serve as a potential marker in the clinic. —CM

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy

CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200+ Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R-/- mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R-/- or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ+ and TNF-α+ T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R-/- tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R-/- mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution.

/pdf/cd200-blockade-modulates-tumor-immune-microenvironment-but-1dj0udw6c9.pdf

CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a Murine Model of Melanoma.

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CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a Murine Model of Melanoma.