Tumor-Infiltrating Programmed Death Receptor-1+ Dendritic Cells Mediate Immune Suppression in Ovarian Cancer

Krempski, James; Karyampudi, Lavakumar; Behrens, Marshall D.; Erskine, Courtney L.; Hartmann, Lynn C.; Dong, Haidong; Goode, Ellen L.; Kalli, Kimberly R.; Knutson, Keith L.

doi:10.4049/jimmunol.1100274

Cited by 222 publications

(231 citation statements)

References 56 publications

Supporting

Mentioning

210

Contrasting

Unclassified

Order By: Relevance

“…T cell suppressor function of these regDCs appeared to be mediated by T cellassociated PD-1 [96]. In contrast, ligation of PD-1 expressed on the tumor-associated DCs suppressed NF-κB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules, revealing a novel role of tumor infiltrating PD-1 + B7-H1 + regDCs in mediating immune suppression in ovarian cancer.…”

Section: Additional Tolerogenic Pathways In Regdcsmentioning

confidence: 88%

“…Recent studies suggest that the B7-H1 ligand, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates DC function in the tumor. New data show that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1 [96]. These dual-positive PD-1 + B7-H1 + DCs have a classical DC phenotype, but are immature, suppressive, and respond poorly to danger signals.…”

Section: Additional Tolerogenic Pathways In Regdcsmentioning

confidence: 99%

See 1 more Smart Citation

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Shurin

2013

Cancer Microenvironment

View full text Add to dashboard Cite

Three major functional subsets of dendritic cells (DCs) have been described in the tumor microenvironment in patients with cancer and tumor-bearing animals: (i) conventional DCs with intact antigen-presenting capabilities, (ii) functionally defective DCs with decreased motility and low ability to uptake, process and present antigens or produce cytokines and (iii) regulatory DCs with high capacity to suppress T cell proliferation, induce differentiation of regulatory T cells or support immune tolerance. Phenotypic characteristics of regulatory DCs (regDCs), as well as the mechanisms of T cell inhibition, vary in different experimental conditions and environments, suggesting high level of their plasticity and probably different origin. Although new data demonstrate that regDCs may play an important role at early stages of tumor development, functional differences and clinical significance of emergence of different myeloid regulatory cells (MDSCs, regDCs, M2 macrophages, N2 neutrophils, mast cells) in cancer remain to be determined.

show abstract

Section: Additional Tolerogenic Pathways In Regdcsmentioning

confidence: 88%

Section: Additional Tolerogenic Pathways In Regdcsmentioning

confidence: 99%

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Shurin

2013

Cancer Microenvironment

View full text Add to dashboard Cite

show abstract

“…43). Indeed, tumor-infiltrating PD-1 þ DCs have been shown to suppress T-cell activity in a mouse model of ovarian cancer (44); whether such cells also influence antitumor immunity in human HGSC awaits further study. Thus, although the PD-1-PD-L1 pathway is thought to be most relevant to CD4 and CD8 T cells, other immune cell types might also be influenced by this regulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Webb

Milne

Nelson

2015

Cancer Immunology Research

170

141

View full text Add to dashboard Cite

a E (CD103)b 7 is a TGFb-regulated integrin that mediates retention of lymphocytes in peripheral tissues by binding to E-cadherin expressed on epithelial cells. We recently reported that a E (CD103)b 7 specifically demarcates intraepithelial CD8 þ tumor-infiltrating lymphocytes (CD8 TIL) in ovarian cancer and that CD103 þ TIL have a surface profile consistent with an active effector phenotype (HLA-DR þ , Ki67 þ , and CD127 lo ). These findings led us to hypothesize that, over time, CD103-mediated retention of CD8 TIL within the tumor epithelium might result in chronic stimulation by tumor antigen, which in turn might lead to an exhausted phenotype. To investigate this possibility, we evaluated PD-1 expression in a large cohort of ovarian tumors (N ¼ 489) with known CD103 þ TIL content. PD-1 þ cells were present in 38.5% of high-grade serous carcinomas (HGSC), but were less prevalent in other histologic subtypes. PD-1 þ TIL were strongly associated with increased disease-specific survival in HGSC (HR, 0.4864; P ¼ 0.0007). Multicolor immunohistochemistry and flow cytometry revealed a high degree of PD-1 and CD103 coexpression, specifically within the CD8 TIL compartment. PD-1 þ CD103 þ CD8 TIL were quiescent when assessed directly ex vivo yet were capable of robust cytokine production after pharmacologic stimulation. Moreover, they showed negligible expression of additional exhaustion-associated markers, including TIM-3, CTLA-4, and LAG-3. Thus, as hypothesized, CD103 þ CD8 TIL express PD-1 and appear quiescent in the tumor microenvironment. However, these cells retain functional competence and demonstrate strong prognostic significance. We speculate that, after standard treatment, PD-1 þ CD103 þ CD8 TIL might regain functional antitumor activity, an effect that potentially could be augmented by immune modulation. Cancer Immunol Res; 3(8); 926-35. Ó2015 AACR.

show abstract

“…5). Of note, immature/tolerogenic DCs are known to mediate immunosuppressive functions by expressing, e.g., inhibitory programmed death (PD)-ligands 1 and 2 that negatively regulate T-cell priming (38,49).…”

Section: Discussionmentioning

confidence: 99%

“…A similar trend was observed with regard to CD80-single-positive DCs. Immature DCs lacking activation markers can abrogate antigen presentation in lymph nodes and antitumor T-cell responses in tumors (37,38). Potentially counteracting this effect, Ad5/3-D24-tras showed the highest ratio of activated versus immature DCs (0.63 vs. 0.31 in mock), and lower absolute amounts of immature CD11c þ CD80 À CD40 À DCs seemed to again depend on the presence of NK cells that mediate their editing (P ¼ 0.092, both comparisons).…”

Section: Treatment With Trastuzumab-coding Oncolytic Adenovirus Resulmentioning

confidence: 99%

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

Liikanen

Tähtinen

Guse

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with fulllength trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-D24-tras, coding for human trastuzumab antibody heavy-and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-D24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-D24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-D24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-D24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. Ó2016 AACR.

show abstract

Tumor-Infiltrating Programmed Death Receptor-1+ Dendritic Cells Mediate Immune Suppression in Ovarian Cancer

Cited by 222 publications

References 56 publications

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

Contact Info

Product

Resources

About