Kimberly R. Kalli

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Data from Accumulation of Memory Precursor CD8 T Cells in Regressing Tumors following Combination Therapy with Vaccine and Anti-PD-1 Antibody

Lavakumar Karyampudi Purushottam Lamichhane Adam D. Scheid Kimberly R. Kalli Barath Shreeder

<div>AbstractImmunosuppression in the tumor microenvironment blunts vaccine-induced immune effectors. PD-1/B7-H1 is an important inhibitory axis in the tumor microenvironment. Our goal in this study was to determine the effect of blocking this inhibitory axis during and following vaccination against breast cancer. We observed that using anti-PD-1 antibody and a multipeptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain, and β-catenin) as a combination therapy regimen for the treatment of breast cancer–bearing mice prolonged the vaccine-induced progression-free survival period. This prolonged survival was associated with increase in number of Tc1 and Tc2 CD8 T cells with memory precursor phenotype, CD27+IL-7RhiT-betlo, and decrease in number of PD-1+ dendritic cells (DC) in regressing tumors and enhanced antigen reactivity of tumor-infiltrating CD8 T cells. It was also observed that blockade of PD-1 on tumor DCs enhanced IL-7R expression on CD8 T cells. Taken together, our results suggest that PD-1 blockade enhances breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the tumor microenvironment. Given the recent success of anti-PD-1 monotherapy, our results are encouraging for developing combination therapies for the treatment of patients with cancer in which anti-PD-1 monotherapy alone may be ineffective (i.e., PD-L1–negative tumors). Cancer Res; 74(11); 2974–85. ©2014 AACR.</div>

10.1158/0008-5472.c.6505149.v1

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Data from PD-1 Blunts the Function of Ovarian Tumor–Infiltrating Dendritic Cells by Inactivating NF-κB

Lavakumar Karyampudi Purushottam Lamichhane James Krempski Kimberly R. Kalli Marshall D. Behrens

<div>AbstractThe PD-1:PD-L1 immune signaling axis mediates suppression of T-cell–dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8−CD209a+) and human (CD1c+CD19−) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB–dependent cytokine release in a SHP-2–dependent manner. Conversely, inhibition of NF-κB–mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. Cancer Res; 76(2); 239–50. ©2015 AACR.</div>

10.1158/0008-5472.c.6507603.v1

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Prognostic and Therapeutic Relevance of Molecular Subtypes in High-Grade Serous Ovarian Cancer

JNCI Journal of the National Cancer Institute (2014)

Gottfried E. Konecny Chen Wang Habib Hamidi Boris Winterhoff Kimberly R. Kalli

Molecular classification of high-grade serous ovarian cancer (HGSOC) using transcriptional profiling has proven to be complex and difficult to validate across studies. We determined gene expression profiles of 174 well-annotated HGSOCs and demonstrate prognostic significance of the prespecified TCGA Network gene signatures. Furthermore, we confirm the presence of four HGSOC transcriptional subtypes using a de novo classification. Survival differed statistically significantly between de novo subtypes (log rank, P = .006) and was the best for the immunoreactive-like subtype, but statistically significantly worse for the proliferative- or mesenchymal-like subtypes (adjusted hazard ratio = 1.89, 95% confidence interval = 1.18 to 3.02, P = .008, and adjusted hazard ratio = 2.45, 95% confidence interval = 1.43 to 4.18, P = .001, respectively). More prognostic information was provided by the de novo than the TCGA classification (Likelihood Ratio tests, P = .003 and P = .04, respectively). All statistical tests were two-sided. These findings were replicated in an external data set of 185 HGSOCs and confirm the presence of four prognostically relevant molecular subtypes that have the potential to guide therapy decisions.

Clinical Significance

Serous ovarian cancer

10.1093/jnci/dju249

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Tables S1-S3 and Figures S1-S2 from APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma

Brandon Leonard Gabriel J. Starrett Matthew J. Maurer Ann L. Oberg Mieke Van Bockstal

Table S1 has RTqPCR primers and probe information. Table S2 has clinical information for the Dutch cohort. Table S3 has a summary of TCGA samples used in our analyses. Figure S1 has RTqPCR assay validation data. Figure S2 shows clinical correlations of APOBEC3G expression in independent cohorts.

10.1158/1078-0432.22463711.v1

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Supplementary Figure 1 from Dual HER/VEGF Receptor Targeting Inhibits In Vivo Ovarian Cancer Tumor Growth

Marc A. Becker Thahir Farzan Sean C. Harrington James Krempski S. John Weroha

PDF - 32KB, No significant change in body weight was observed throughout the experimental duration.

10.1158/1535-7163.22498824.v1

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Supplementary Figure Legend from Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer

S. John Weroha Marc A. Becker Sergio Enderica-Gonzalez Sean C. Harrington Ann L. Oberg

PDF file - 76K

Legend

10.1158/1078-0432.22448627

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Supplementary Info from PD-1 Blunts the Function of Ovarian Tumor–Infiltrating Dendritic Cells by Inactivating NF-κB

Lavakumar Karyampudi Purushottam Lamichhane James Krempski Kimberly R. Kalli Marshall D. Behrens

Supplementary methods and figures. Fig. 1:TIDCs obtained from the ascites from ovarian cancer patients express PD-1 mRNA. Fig. 2: TIDCs obtained from the ascites of ID8 tumor bearing mice express PD-1 mRNA.

Ovarian tumor

10.1158/0008-5472.22408743

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MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Mayo Clinic Proceedings (2018)

Matthew S. Block Robert A. Vierkant Peter Rambau Stacey J. Winham Philipp Wagner

ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and MethodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).ConclusionResults are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

Tissue microarray

10.1016/j.mayocp.2017.10.023

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Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome

BMC Medical Genomics (2014)

Brooke L. Fridley Sebastian M. Armasu Mine Cicek Melissa C. Larson Chen Wang

Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions. We examined blood-based DNAm in 336 EOC cases and 398 controls; we included only high-quality CpG loci that did not show evidence of association with white blood cell type distributions to evaluate association with case status and overall survival. Of 13,816 CpGs, no significant associations were observed with survival, although eight CpGs associated with survival at p < 10-3, including methylation within a CpG island located in the promoter region of GABRE (p = 5.38 x 10-5, HR = 0.95). In contrast, 53 CpG methylation sites were significantly associated with EOC risk (p <5 x10-6). The top association was observed for the methylation probe cg04834572 located approximately 315 kb upstream of DUSP13 (p = 1.6 x10-14). Other disease-associated CpGs included those near or within HHIP (cg14580567; p =5.6x10-11), HDAC3 (cg10414058; p = 6.3x10-12), and SCR (cg05498681; p = 4.8x10-7). We have identified several CpGs in leukocytes that are differentially methylated by case-control status. Since a retrospective study design was used, we cannot differentiate whether DNAm was etiologic or resulting from EOC; thus, prospective studies of EOC-associated loci are the critical next step.

Human genetics

10.1186/1755-8794-7-21

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Identification of a broad coverage HLA-DR degenerate epitope pool derived from carcinoembryonic antigen

Cancer Immunology Immunotherapy (2009)

Lavakumar Karyampudi Christopher J. Krco Kimberly R. Kalli Courtney L. Erskine Lynn C. Hartmann

Carcinoembryonic antigen

ELISPOT

10.1007/s00262-009-0738-z

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Citations (12)