CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

Byrne, Katelyn T.; Vonderheide, Robert H.

doi:10.1016/j.celrep.2016.05.058

Cited by 230 publications

(254 citation statements)

References 73 publications

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“…This observation was also true in our subcutaneous, implantable murine model of PDA. This subcutaneous model faithfully recapitulated the histology, immune infiltration, and even response to therapy of spontaneous KPC pancreatic tumors (8,11,12). Another group used the spontaneous, autochthonous KPC model and reported similar conclusions to those presented in this paper (19).…”

Section: Discussionmentioning

confidence: 69%

“…We therefore compared the expression of Cxcl5 via RT-qPCR in 4662 KPC cells treated with U0126 (a MEK1/2 inhibitor) or DMSO. The 4662 cell line is a well-characterized KPC-derived PDA cell line that has been previously described (8,11,42). Inhibition of MEK resulted in a significant increase in Cxcl5 expression compared to control (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Rosa LSL-YFP ;Pdx1-Cre (KPCY) and Kras LSL-G12D/+ ;Trp53 LSL-R172H/+ ;Pdx1-Cre (KPC) mice were bred in-house and backcrossed for over ten generations with C57BL/6J mice (6,38). All of these mice were confirmed on the C57BL/6 background at the DartMouse™ Speed Congenic Core Facility at the Giesel School of Medicine at Dartmouth College (11). Four- to six- months old KPC/KPCY mice with palpable tumors or with tumors >100mm 3 by ultrasound were used in this study, with their age-matched controls.…”

Section: Methodsmentioning

confidence: 99%

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CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma

Chao

Furth

Vonderheide

2016

Cancer Immunology Research

206

161

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Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas. Using a genetically engineered mouse model of PDA, we found that tumor and stromal cells differentially expressed CXCR2 ligands, with Cxcl5 high in tumor and Cxcl2 high in stroma. Cxcl5 expression was associated with mutant Kras expression and regulated by NF-κB activation. Host CXCR2 inhibition by genetic ablation prevented neutrophil accumulation in pancreatic tumors and led to a T cell–dependent suppression of tumor growth. In the absence of neutrophils, activated and functional T cells infiltrated pancreatic tumors otherwise devoid of effector T cells. Thus, the CXCR2-ligand axis helps establish an immunosuppressive microenvironment in PDA, highlighting the potential utility of targeting this axis as a novel therapy for this deadly disease.

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Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma

Chao

Furth

Vonderheide

2016

Cancer Immunology Research

206

161

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“…We do not mean to suggest antigen gene therapy as the translational step supported by our findings; rather, combinations of vaccines with inhibition of tumor and host immune suppression are the high priority strategies in PDA (44). In the KPC model, for example, the combination of chemotherapy and agonist CD40 mAb synergizes to generate durable remissions and T cell memory in the absence of neoepitopes (45), data supporting a new clinical trial in patients with metastatic pancreatic cancer (NCT02588443).…”

Section: Discussionmentioning

confidence: 99%

Lack of immunoediting in murine pancreatic cancer reversed with neoantigen

Evans¹,

Diamond²,

Rech³

et al. 2016

JCI Insight

137

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In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through “immunoediting,” whereby tumors adapt to immune pressure and escape T cell–mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. Spontaneous tumor progression was identical in the presence or absence of T cells. Moreover, tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. However, introduction of the neoantigen ovalbumin (OVA) led to tumor rejection and T cell memory, but this did not occur in OVA immune-tolerant mice. Thus, immunoediting does not occur in this mouse model — a likely consequence, not a cause, of absent neoepitopes. Because many human tumors also have a low missense mutational load and minimal neoepitope burden, our findings have clinical implications for the design of immunotherapy for patients with such tumors.

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“…þ Tregs in tumor models after either anti-CSF-1R or anti-CD40 treatment (40,41). We assessed whether similar changes were observed in this subset of CD4 þ T cells after peptide.…”

Section: Previous Reports Described Decreased Immunosuppressive Foxp3mentioning

confidence: 99%

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

Wiehagen

Girgis

Yamada

et al. 2017

Cancer Immunology Research

134

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Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu. Anti-CD40/anti-CSF-1R-treated tumors contain decreased tumor-associated macrophages and Foxp3 þ regulatory T cells. This combination approach increases maturation and differentiation of proinflammatory macrophages and dendritic cells and also drives potent priming of effector T cells in draining lymph nodes. As a result, tumor-infiltrating effector T cells exhibit improved responses to tumor antigen rechallenge. These studies show that combining therapeutic approaches may simultaneously remove inhibitory immune populations and sustain endogenous antitumor immune responses to successfully impair cancer progression.

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CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

Cited by 230 publications

References 73 publications

CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma

CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma

Lack of immunoediting in murine pancreatic cancer reversed with neoantigen

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

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