Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells

Beavis, Paul A.; Henderson, Melissa A.; Giuffrida, Lauren; Davenport, Alexander J.; Petley, Emma V.; House, Imran G.; Lai, Junyun; Sek, Kevin; Milenkovski, Nicole; John, Liza B.; Mardiana, Sherly; Slaney, Clare Y.; Trapani, Joseph A.; Loi, Sherene; Kershaw, Michael H.; Haynes, Nicole M.; Darcy, Phillip K.

doi:10.1158/2326-6066.cir-18-0291

Cited by 53 publications

(52 citation statements)

References 56 publications

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“…Single cell mass spectrometry analyses of PBMC from patients with advanced melanoma, before and after anti-PD-1 therapy revealed that CD141 and CD11c, both expressed by cDC1 are strong predictive biomarkers of clinical response to anti-PD-1 treatments [122]. This is consistent with several mouse studies reporting that cDC1-deficient mice do not respond to immune checkpoint blockade using anti-PD-L1 or a combination of anti-PD-1 anti-CTLA4 mAb [123,124]. Furthermore, mice that possess cDC1 defective in antigen crosspresentation fail to establish CTL responses and do not respond to anti-PD-1 blockade [125].…”

Section: And Pd-1supporting

confidence: 86%

Dendritic Cells and Their Roles in Anti-Tumour Immunity

Pang¹,

Macri²,

Patton³

et al. 2020

Current Cancer Treatment

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Dendritic cells are rare cells found in blood and throughout all organs of the body as resident or migrating cell populations. Dendritic cells sense danger signals of pathogens and host cell stress through pattern receptors expressed on the cell surface and within organelles of the cell. Ligation of these receptors leads to activation and production of many different chemokines, cytokines and interferons. Key to the function of dendritic cells is their potent capacity to present antigen and activate naïve T cells. These qualities, potent antigen presentation and cytokine production together allow the dendritic cells to be at the forefront of danger responses, linking innate and adaptive immunity. Research over the last 20 years has clarified a role of dendritic cells in anti-tumour responses, and their location within the tumour environment is clear, with both deleterious and beneficial correlations, depending on the subset and tumour type. Harnessing the qualities of dendritic cells to increase anti-tumour immunity is the ultimate goal, although this will require extensive knowledge of different dendritic cell subsets and their regulation through immune checkpoints.

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Section: And Pd-1supporting

confidence: 86%

Dendritic Cells and Their Roles in Anti-Tumour Immunity

Pang¹,

Macri²,

Patton³

et al. 2020

Current Cancer Treatment

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“…Specifically, dysfunctional CD4 + T cells appear to express higher levels of CTLA4 at late time points in their activation cycle than their CD8 + counterparts. This may partially explain why, in many murine cancer models, ICB with anti‐CTLA4 alone or in combination with anti‐PD1 induces the expansion of a T H 1‐like subset of CD4 + T cells 73,74 . Whether this expansion is the result of a “rescue” of dysfunctional CD4 + T cells or the priming of novel clonotypes requires further investigation.…”

Section: Help In Therapeutic Contextmentioning

confidence: 99%

“…This may partially explain why, in many murine cancer models, ICB with anti-CTLA4 alone or in combination with anti-PD1 induces the expansion of a T H 1-like subset of CD4 + T cells. 73,74 Whether this expansion is the result of a "rescue" of dysfunctional CD4 + T cells or the priming of novel clonotypes requires further investigation. Combination treatments employing NeoAg vaccines and ICB will likely yield optimal responses by overcoming exhaustion of newly primed clones.…”

Section: Immune Checkpoint Blockadementioning

confidence: 99%

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Brightman

Naradikian

Miller

et al. 2020

Journal of Leukocyte Biology

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The goal of precision immunotherapy is to direct a patient's T cell response against the immunogenic mutations expressed on their tumors. Most immunotherapy approaches to‐date have focused on MHC class I‐restricted peptide epitopes by which cytotoxic CD8+ T lymphocytes (CTL) can directly recognize tumor cells. This strategy largely overlooks the critical role of MHC class II‐restricted CD4+ T cells as both positive regulators of CTL and other effector cell types, and as direct effectors of antitumor immunity. In this review, we will discuss the role of neoantigen specific CD4+ T cells in cancer immunotherapy and how existing treatment modalities may be leveraged to engage this important T cell subset.

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“…After 30‐ to 45‐min digestion at 37 °C, cells were filtered twice (70 μm) and erythrocytes were lysed with ACK (ammonium–chloride–potassium) buffer. For detection of IFNγ production by T cells and NK cells ex vivo, TILs were stimulated with PMA/ionomycin in the presence of GolgiPlug (BD Pharmingen, Franklin Lakes, NJ, USA) and GolgiStop (BD Pharmingen) as described previously . Samples were incubated with fluorescently conjugated antibodies in 2.4G2 Fc blocking antibody.…”

Section: Methodsmentioning

confidence: 99%

“…For detection of IFNc production by T cells and NK cells ex vivo, TILs were stimulated with PMA/ionomycin in the presence of GolgiPlug (BD Pharmingen, Franklin Lakes, NJ, USA) and GolgiStop (BD Pharmingen) as described previously. 64 Samples were incubated with fluorescently conjugated antibodies in 2.4G2 Fc blocking antibody. Fixable yellow (Invitrogen) was used to determine viable cells.…”

Section: Analysis Of Immune Cell Subsets/ex Vivo Tumor Cells By Flow mentioning

confidence: 99%

Tissue‐specific tumor microenvironments influence responses to immunotherapies

et al. 2019

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Objectives Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue‐specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. Methods We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. Results Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid‐derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD‐1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. Conclusion Taken together, these data demonstrate that tissue‐specific TMEs influence immunotherapy responses and highlight the importance in defining tissue‐specific response patterns in patients.

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Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3− Cell–Mediated Modulation of CD103+ Dendritic Cells

Cited by 53 publications

References 56 publications

Dendritic Cells and Their Roles in Anti-Tumour Immunity

Dendritic Cells and Their Roles in Anti-Tumour Immunity

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

Tissue‐specific tumor microenvironments influence responses to immunotherapies

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