Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

Efremova, Mirjana; Rieder, Dietmar; Klepsch, Victoria; Charoentong, Pornpimol; Finotello, Francesca; Hackl, Hubert; Hermann-Kleiter, Natascha; Löwer, Martin; Baier, Gottfried; Krogsdam, Anne; Trajanoski, Zlatko

doi:10.1038/s41467-017-02424-0

Cited by 200 publications

(183 citation statements)

References 63 publications

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“…Although one could propose that variation in the overall microbiota composition may appear after the arrival of mice in our animal facility, we never observed any "box-effect" that would lend support to such a hypothesis. Besides, given the key contribution of immunity to CRC tumor rejection in B6 mice, we hypothesized that an in vivo clonal selection may occur in the colon of mice leading to the enrichment of "immune-resistant" tumor cell clones, able to escape immunity, in the CRC-progressive group vs. "immune-sensitive" tumor cell clones in the CRC-rejecting group [16]. However, we found that regardless of their origin, tumor cells behaved similarly and generated both the progressive and rejecting CRC development profiles after re-implantation in naïve B6 mice.…”

Section: Discussionmentioning

confidence: 99%

“…In order to study the impact of colon location and the involvement of the immune microenvironment in tumor development, we relied on a pre-clinical immunocompetent orthotopic CRC mouse model. In this model, we used the C57BL/6 (B6)-background MC38 murine CRC cell line [15], recently characterized as a model for hypermutated/MSI CRC [16], that has been genetically engineered to express firefly Luciferase (MC38-fLuc). MC38-fLuc cells were implanted into the caecum (IC) of immunocompetent B6 mice, which allowed us to follow tumor development over time using a bioluminescence camera as well as the dynamic of tumor-infiltrating immune cells by flow cytometry and transcriptomic analyses.…”

Section: Introductionmentioning

confidence: 99%

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Colon-specific immune microenvironment regulates cancer progression versus rejection

Trimaglio

Tilkin–Mariamé

Féliu

et al. 2020

Preprint

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Background:Immunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset of patients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissue-specific factors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironment shapes the immune response to CRC is needed to identify mechanisms of resistance to immunotherapies and guide the development of novel therapeutics. Methods:In an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescence imaging and the immune signatures were assessed at a transcriptional level using NanoString and at a cellular level by flow cytometry.Results: Despite initial tumor growth in all mice, only 25 to 35% of mice developed a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor.No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injected in non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumors exhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernible shortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting mice presented an early inflammatory response and an antitumor microenvironment enriched in CD8 + T cells. Conclusions:Taken together, our data demonstrate the role of the colon microenvironment in regulating the balance between anti or protumor immune responses. While emphasizing the relevance of the CRC orthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancer response to immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Colon-specific immune microenvironment regulates cancer progression versus rejection

Trimaglio

Tilkin–Mariamé

Féliu

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…[ 7 ] Therefore, rendering these tumors sensitive to immunotherapy remains a major challenge, [ 6 ] and using immunostimulatory agents could be a complementary approach to improve cancer treatment with checkpoint inhibitors. Murine colon cancer cell line, CT26, one of the most extensively used syngeneic mouse tumor models that lack mutations in mismatch repair genes, [ 13‐15 ] was chosen for the present study.…”

Section: Figurementioning

confidence: 99%

Immunostimulatory TLR7 Agonist‐Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy

Huang

Mendez

Echeagaray

et al. 2020

Advanced Therapeutics

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Mono‐ or dual‐checkpoint inhibitors for immunotherapy have changed the paradigm of cancer care; however, only a minority of patients responds to such treatment. Combining small molecule immunostimulators can improve treatment efficacy, but they are restricted by poor pharmacokinetics. In this study, conjugated TLR7 agonists onto silica nanoparticles show extended drug localization after intratumoral injection. The nanoparticle‐based TLR7 agonist increases immune stimulation by activating the TLR7 signaling pathway. When treating CT26 colon cancer, nanoparticle conjugated TLR7 agonists increase T cell infiltration into the tumors by >4× and upregulate expression of the interferon γ gene compared to its unconjugated counterpart by ≈2×. Toxicity assays establish that the conjugated TLR7 agonist is a safe agent at the effective dose. When combined with checkpoint inhibitors that target programmed cell death protein 1 (PD‐1) and cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), a 10–100× increase in immune cell migration is observed; furthermore, 100 mm3 tumors are treated, and a 60% remission rate is observed including remission at contralateral noninjected tumors. The data show that nanoparticle‐based TLR7 agonists are safe and can potentiate the effectiveness of checkpoint inhibitors in immunotherapy resistant tumor models and promote a long‐term specific memory immune function.

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“…IFNg binding to the IFNg-receptor (Ifngr) initiates a signaling cascade through the kinases JAK1/2 and the transcription factors STAT1/3 to induce the expression of diverse genes involved in antigen processing and presentation, as well as genes encoding the heavy and light chain of MHC-I. Importantly, IFNg also results in the expression of the immunosuppressive marker PD-L1 on the surface of tumor cells which serves as a ligand for the PD-1 receptor on T cells to attenuate antitumor immune responses (30,31). In contrast to canonical IFNg-stimulated antigen presentation, exposure to Hsp90i did not alter transcript levels of MHC-I heavy chains H2-K1 and H2-D1 or the light chain beta-2-microglobulin (B2m), indicating that Hsp90i induces antigen presentation through a distinct mechanism (Fig.…”

Section: Hsp90i Stimulates Mhc-i Antigen Presentation Independent Of mentioning

confidence: 99%

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Jaeger

Stopfer

Lee

et al. 2019

Clinical Cancer Research

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Purpose: Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.Results: We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNgindependent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic nonheat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.Conclusions: These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.See related commentary

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Targeting immune checkpoints potentiates immunoediting and changes the dynamics of tumor evolution

Cited by 200 publications

References 63 publications

Colon-specific immune microenvironment regulates cancer progression versus rejection

Colon-specific immune microenvironment regulates cancer progression versus rejection

Immunostimulatory TLR7 Agonist‐Nanoparticles Together with Checkpoint Blockade for Effective Cancer Immunotherapy

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

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