University of Pittsburgh Cancer Institute (UPCI)

Cancer Immunology and Tumor Microenvironment

The focus of this research theme is to understand the complex interactions between components of the immune system and tumors and their microenvironment, immunosuppression in tumor-bearing individuals, and escape of tumors from immunological control.

Selected Publications

  • Human leukocyte antigen (HLA) class I antigen processing machinery (APM) component downregulation permits escape of malignant cells from recognition by cytotoxic T lymphocytes (CTL) and correlates with poor prognosis in patients with head and neck cancer (HNC). Activated STAT1 (pSTAT1) is necessary for APM component expression in HNC cells. A study by CIP members found that the phosphatase SHP2 was significantly upregulated in HNC tissues, and that SHP2 depletion in HNC cells significantly upregulated expression of pSTAT1 and HLA class I APM components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited IFN-γ-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor cells did not significantly induce IFN-γ-mediated APM component expression, verifying STAT1 dependence of SHP2 activity. SHP2 depletion induced recognition of HNC cells by HLA class I-restricted CTL and secretion of inflammatory, T-cell attracting chemokines, RANTES and IP10. These findings suggest that targeting SHP2 may enhance T-cell-based cancer immunotherapy. (Leibowitz et. al., Clin Cancer Res. 2013 Feb 15;19(4):798-808.)
  • Pancreatic ductal adenocarcinoma (PDA) has an aggressive natural history and is resistant to therapy. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor for many damage-associated molecular pattern molecules. RAGE is overexpressed in both human and murine models of PDA as well as most advanced epithelial neoplasms. The immunosuppressive nature of the PDA microenvironment is facilitated, in part, by the accumulation of regulatory immune cell infiltrates such as myeloid-derived suppressor cells (MDSCs). To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple-transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice had markedly delayed pancreatic carcinogenesis and a significant diminution of MDSCs compared with KC mice at comparable time points post-weaning. Although RAGE was not required for the development or suppressor activity of MDSCs, its absence was associated with temporally limited pancreatic neoplasia and altered phenotype and function of the myeloid cells. In lieu of MDSCs, KCR animals at comparable time points exhibited mature CD11b(+)Gr1(-)F4/80(+) cells that were not immunosuppressive in vitro. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6. (Vernon et. al., J Immunol. 2013 Feb 1;190(3):1372-9.)
  • Human beta-defensins (hBDs) are antimicrobial peptides that have an important role in innate immune responses at epithelial barriers such as the skin. However, the role that hBDs have in initiating cellular immune responses that contribute to antigen-specific adaptive immunity is not well understood. A CIP study showed that one member of the hBD family, hBD3, could induce maturation and T-helper type 1 skewing function in human Langerhans cell-like dendritic cells (LC-DCs). Specifically, hBD3 potently induced phenotypic maturation of LC-DCs, including increased expression of CCR7, which mediated functional chemotactic responses to CCL19 and CCL21. hBD3-stimulated LC-DCs induced strong proliferation of and IFN-γ secretion by naive human T cells. hBD3 also induced phenotypic maturation of primary human skin-migratory DCs derived from human skin explants. These results suggested an important role for hBD3 in inducing DC activation, migration, and polarization. (Ferris et. al., J Invest Dermatol. 2013 Feb;133(2):460-8.)

Members

Bartlett, David, MD
Surgery
Lu, Binfeng, MD, MS
Immunology
Binder, Robert, PhD
Immunology
Morel, Penelope, MD
Immunology
Borghesi, Lisa, PhD
Immunology
Rabinowich, Hannah, PhD
Pathology
Butterfield, Lisa, PhD
Medicine
Ray, Anuradha, PhD
Medicine
de Vallejo, Abbe, PhD
Pediatrics (CHP)
Salter, Russell, PhD
Immunology
Delgoffe, Greg, PhD
Immunology
Shlomchik, Mark, MD, PhD
Immunology
Donnenberg, Albert, PhD
Medicine
Shurin, Michael, MD
Pathology
Ferris, Robert L., MD, PhD, FACS
Otolaryngology
Storkus, Walter, PhD
Dermatology
Finn, Olivera, PhD
Immunology
Szabolcs, Paul, MD
Pediatrics (CHP)
Gaffen, Sarah, PhD
Medicine
Thomson, Angus, PhD, DSc
Surgery
Kalinski, Pawel, MD, PhD
Surgery
Vignali, Dario A., PhD
Immunology
Kane, Lawrence, PhD
Immunology
Vujanovic, Nikola, MD, PhD
Pathology
Lakkis, Fadi, MD
Surgery
Whiteside, Theresa, PhD
Pathology
Larregina de Morelli, Adriana, MD, PhD
Dermatology
Zeh, Herbert, MD
Surgery
Lotze, Michael, MD
Surgery