University of Pittsburgh Cancer Institute (UPCI)

Cancer Immunotherapy

Dendritic Cell The focus of this research theme is to develop more effective ways to stimulate innate and adaptive immune responses to human tumors and to evaluate the efficacy of therapeutic strategies based on such approaches in better animal models of human cancer, and to identify candidate immune biomarkers and state-of-the-art immunomonitoring assays to detect therapeutically effective immune modulation.

Selected Publications

  • Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. In a cross-sectional study examining effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients, it was found that CRT decreased the frequency of circulating CD4(+) T cells (P < 0.002) but increased that of CD4(+)CD39(+) Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to activation-induced cell death or cisplatin but conventional CD4(+) T cells (Tconv) were not. CRT-induced Treg from HNSCC patients or healthy donors upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax. Thus, highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC. (Schuler et. al., Clin Cancer Res. 2013 Dec 1;19(23):6585-96.)
  • Although regulatory T cells (Treg) are highly enriched in human tumors compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg in these two sites remains undefined. In this study, tumor-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg. These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ. (Jie et. al., Br J Cancer. 2013 Nov 12;109(10):2629-35.)
  • Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8(+) CTL and FcγR in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. CIP members determined that, in cetuximab-treated patients with head and neck cancer (HNC), cetuximab-activated natural killer (NK) cells promote dendritic cell (DC) maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and TH1 cytokine release through "NK-DC cross-talk." FcγRIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. (Srivastava et. al., Clin Cancer Res. 2013 Apr 1;19(7):1858-72.)

Members

Bartlett, David, MD
Surgery
Lotze, Michael, MD
Surgery
Binder, Robert, PhD
Immunology
Shurin, Michael, MD
Pathology
Butterfield, Lisa, PhD
Medicine
Storkus, Walter, PhD
Dermatology
Ferris, Robert L., MD, PhD, FACS
Otolaryngology
Szabolcs, Paul, MD
Pediatrics (CHP)
Finn, Olivera, PhD
Immunology
Vignali, Dario A., PhD
Immunology
Kalinski, Pawel, MD, PhD
Surgery
Whiteside, Theresa, PhD
Pathology
Larregina de Morelli, Adriana, MD, PhD
Dermatology
Zeh, Herbert, MD
Surgery