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Characterizing and Modulating the Tumor Microenvironment in Renal Cell Carcinoma: Potential Therapeutic Strategies

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Abstract

It has long been known that conventional strategies to curtail cell growth and proliferation (such as cytotoxic therapy) are not particularly effective in the setting of renal cell carcinoma (RCC). In recent years, translational efforts have yielded effective therapies predicated on the biology of the disease. Examples of this include cytokine therapy (i.e., interferon-α and interleukin-2) and angiogenesis inhibitors (i.e., sorafenib, sunitinib, pazopanib, and bevacizumab). While these agents have drastically altered the landscape of therapy for metastatic RCC, none of these options are curative. A major focus of investigation in recent years has been the complex interplay between tumor and its associated microenvironment. Although existing agents such as sunitinib may modulate this interplay to some extent, direct targeting of the tumor microenvironment is a promising strategy. This chapter serves to outline moieties that play a putative role in modulating immune cells in the tumor microenvironment. Of particular interest is signal transducer and activator of transcription 3 (Stat3), which appears to drive recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) to sites of tumor, thereby stifling the antitumor immune response. In recent years, pharmacologic strategies to antagonize Stat3 have emerged, including inhibitors of upstream activators Janus kinase 2 (Jak2) and fibroblast growth factor receptor (FGFR). A second, distinct strategy to augment the antitumor immune response is through disruption of cellular interactions that abrogate T-cell activity. Inhibitors of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA4), including BMS-936558 and ipilimumab, appear to propagate T-cell activity, and are in varying stages of clinical development. Any success encountered with these therapies or combinations will underscore the critical importance of targeting not only the tumor itself but also the surrounding microenvironment.

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Authors and Affiliations

  1. Division of Genitourinary Malignancies, Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Sumanta Kumar Pal M.D.

  2. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Karen Reckamp M.D.

  3. Cancer Immunotherapeutics Program, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Hua Yu Ph.D.

  4. Division of Hematology Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA

    Robert A. Figlin M.D., F.A.C.P. (Professor of Medicine and Biomedical Sciences, Director)

  5. Samuel Oschin Comprehensive Cancer Institute, Los Angeles, USA

    Robert A. Figlin M.D., F.A.C.P. (Associate Director for Academic Programs)

  6. David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Robert A. Figlin M.D., F.A.C.P. (Professor Emeritus of Medicine and Urology)

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  1. Sumanta Kumar Pal M.D.
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Correspondence to Sumanta Kumar Pal M.D. .

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Editors and Affiliations

  1. David Geffen School of Medicine at UCLA, Department of Medicine, Cedars-Sinai Medical Center, n/a, Los Angeles, 90095, California, USA

    Robert A. Figlin

  2. Lineberger Comprehensive Cancer Center, University of North Carolina, Campus Box 7295, Room 21-237, 218, Chapel Hill, 27599-7295, North Carolina, USA

    W. Kimryn Rathmell

  3. Taussig Cancer Institute, Department of Solid Tumor Oncology, Cleveland Clinic, 9500 Euclid Ave, CLEVELAND, 44195-0001, Ohio, USA

    Brian I. Rini

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Pal, S.K., Reckamp, K., Yu, H., Figlin, R.A., Figlin, R.A., Figlin, R.A. (2012). Characterizing and Modulating the Tumor Microenvironment in Renal Cell Carcinoma: Potential Therapeutic Strategies. In: Figlin, R., Rathmell, W., Rini, B. (eds) Renal Cell Carcinoma. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-2400-0_11

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