Inhibition of HSPs for Enhanced Immunity

  • Ronald J. Fecek
  • Subhara Raveendran
  • Manoj Chelvanambi
  • Walter J. Storkus
Chapter

Abstract

Heat shock proteins (HSPs) are highly abundant proteins found in all cell types in the body, where they comprise approximately 1–2% of the cellular proteome. Due to the physiologically stressful conditions of the progressive tumor microenvironment (TME, i.e., hypoxia, acidosis, and high interstitial fluid pressure), expression of HSPs in tumor cells can be increased by a factor of two- to tenfold over that found in normal cells. Larger HSPs (HSP70 and HSP90) maintain the structural integrity of a broad range of tumor client proteins associated with oncogenesis and disease progression. HSPs can also be translocated to the tumor cell surface or shed into the extracellular space where they have recently been found to serve as “chaperokines” capable of modulating the function of antigen-presenting cells and immune effector cells. This chapter will provide a summary of the pleiotropic impact of HSPs on tumor immunity and suggest strategies by which HSP inhibitors (HSPi) might be best applied to optimize the antitumor efficacy of combination immunotherapy approaches.

Keywords

Adoptive cellular therapy Cytotoxic T lymphocytes Heat shock protein Histone deacetylase inhibitors HSP inhibitors Immunotherapy Regulatory cells Tumor microenvironment Vaccine Vascular normalization 

Notes

Acknowledgments

This work was supported by NIH R01 CA169118 (WJS) and NIH P50 CA121973 CA (Career Enhancement Award to RJF).

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ronald J. Fecek
    • 1
  • Subhara Raveendran
    • 2
  • Manoj Chelvanambi
    • 3
  • Walter J. Storkus
    • 1
    • 3
    • 4
    • 5
    • 6
    • 7
  1. 1.Department of DermatologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of Human GeneticsUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.Department of BioengineeringUniversity of Pittsburgh School of MedicinePittsburghUSA
  6. 6.University of Pittsburgh Graduate School of Public HealthPittsburghUSA
  7. 7.Melanoma Program of the University of Pittsburgh Cancer InstitutePittsburghUSA

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