The Center for Immunotherapy of Cancer and Infectious Diseases Laboratories Ph.D. Program Clinical Activities News and Events About CICID
UConn Health Center
The Center for Immunotherapy of Cancer and Infectious Diseases Site MapHome
The Center for Immunotherapy of Cancer and Infectious Diseases



Adler Lab

Aguila Lab

Chandawarkar Lab

Li Lab

McElhaney Lab

Srivastava Lab


Clinical Activities
If you have questions call us at 860-679-4444
 PI Labs / Srivastava Lab
Pramod Srivastava
Pramod Srivastava
Professor of Immunology
Physician Health Services Chair in Cancer Immunology
Director, Center for Immunotherapy of Cancer and Infectious Diseases
Director, University Cancer Center
Email:
srivastava@nso2.uchc.edu
This laboratory studies antigen presentation by MHC I molecules and indirect presentation (cross-priming) of antigens from non-antigen presenting cells (APCs) by APCs. We have uncovered a major role for heat shock proteins (HSPs) in these phenomena. These studies have also lead to new approaches to immunotherapy of cancers and infectious diseases and these are being pursued through clinical trials.

Previous studies from the laboratory have uncovered three aspects of the roles of HSPs in immune response (see Srivastava et al. 1998):

    Center for Immunotherapy

  • Homogeneous preparations of certain HSPs such as the gp96 , calreticulin , hsp90 and hsp70 are associated with short peptides derived from range of cellular proteins. These peptides can be from normal self proteins or from mutated or foreign proteins, should the cells from which the heat shock proteins are isolated, express such proteins.

  • If HSPs (which are actually heat shock proteins-peptide complexes) are injected into immunocompetent hosts, the hosts develop potent antigen-specific CD8+ and CD4+ T cells. This response is directed solely at the altered or foreign peptides and not against self peptides not against the HSPs themselves. The immunogenic HSP-peptide complexes may also be reconstituted in vitro from recombinant HSPs and synthetic peptides. These observations are the basis of large number of completed and ongoing clinical trials where the HSP-peptide complexes purified from cancer cells or from virus-infected cells are being used as vaccines against the respective cancers or viruses. That mechanism of immunogenicity of HSP-peptide complexes is largely clear and involves the interaction of the HSPs with macrophage or dendritic cells through the HSP receptor CD91, followed by re-presentation of the HSP-chaperoned peptides by the MHC I and and MHC II molecules of the macrophage or dendritic cells (Figure 1).

  • HSPs stimulate macrophage and dendritic cells in a peptide-independent manner to secrete a range of inflammatory cytokines and to express antigen presenting and co-stimulatory molecules. HSPs also cause maturation of dendritic cells (Figure 1).

 Figure 1

The molecular and cellular mechanisms involved in the three principles outlined above are being investigated in our laboratory and their clinical applications are being explored. It is this laboratory's premise that HSPs play a central role in Innate and adaptive immune responses including in indirect presentation and cross-priming and that these roles can be manipulated effectively for therapy of cancers, infectious diseases and autoimmune disorders.

Selected Publications

  1. Basu S, Srivastava PK. Immunological role of neuronal receptor VR1 expressed on dendritic cells. Proc. Natl. Acad. Sci. USA, 102 (14):5120-5, 2005.

  2. Binder RJ, Srivastava PK. Peptides chaperoned by heat shock proteins are a necessary and sufficient source of antigen in cross-priming CD8+ T cells. Nature Immunology, Advance On-line Publication, 2005.

  3. Srivastava PK. Immunotherapy for Human Cancer Using Heat Shock Protein-Peptide Complexes. Current Medicine, 2005.

  4. Parmiani G, Testori A, Maio M, Castelli C, Rivoltini L, Pilla L, Belli F, Mazzaferro V, Coppa J, Patuzzo R, Sertoli MR, Hoos A, Srivastava PK, Santinami M. Heat shock proteins and their use as anticancer vaccines. Clin. Cancer Res. 10: 8142-8146, 2004.

  5. Pilla L, Patuzzo R, Rivoltini L, Maio M, Pennacchioli E, Lamaj E, Maurichi A, Massarut S, Marchiano A, Santantonio C, Tosi D, Arienti F, Cova A, Sovena G, Piris A, Nonaka D, Bersani I, De Florio A, Srivastava PK, Hoos A, Santinami M, Parmiani G. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes gp96, in combination with GM-CSF and interferon-a in metastatic melanoma patients. Clin. Cancer Res., 2005.

  6. Li Z, Qiao Y, Liu B, Laska EJ, Chakravarthi P, Kulko JM, Bona RD, Fang M, Hegde U, Moyo V, Tannenbaum SH, Ménoret A, Gaffney J, Glynn L, Runowicz CD, Srivastava PKCombination of Imatinib Mesylate with Autologous Leukocyte-Derived Heat Shock Protein 70 Induces Immunologic And Clinical Responses against Chronic Myelogenous Leukemia. Clin. Cancer Res., 2005

  7. Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proc. Natl. Acad. Sci: USA, 101(16):6128-6133, 2004.

  8. Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava PK. Immune modulation with high dose of heat shock protein gp96: Therapy of murine autoimmune diabetes and encephalomyelitis. Intl Immunology, 16 (4):615-624, 2004.

  9. Stebbing J, Gazzard B, Portsmouth S, Gotch F, Kim L, Bower M, Mandalia S, Binder R, Srivastava P, Patterson S. Disease associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor. Blood, 102: 1806 - 1814, 2003.

  10. Basu S, Srivastava PK. Fever-like temperature induces maturation of dendritic cells through induction of hsp90. Intl Immunology, 15(9):1053-61, 2003.

  11. Mazzaferro V, Coppa JC, Carrabba M, Rivoltini L, Schiavo M, Marchianň A, Romito R, Pulvirenti A, Camerini T, Regalia E,Gianessi W, Camerini R, Lewis JJ, Srivastava PK, Parmiani G. Vaccination with autologous tumor derived heat shock protein peptide complex Gp-96 (HSPPC-96) following curative resection of colorectal liver metastases. Clin. Cancer Res., 9(9):3235-45. 2003.

  12. Srivastava PK. Hypothesis : Controlled necrosis as a tool for immunotherapy of human cancer. Cancer Immunity, Vol. 3, pg 4, 2003.

  13. Rivoltini L, Castelli C, Carrabba M, Mazzaferro V, Pilla L, Huber V, Coppa J, Gallino G, Scheibenbogen C, Squarcina P, Cova A, Camerini R, Lewis JJ, Srivastava PK, Parmiani G. Human Tumor-Derived Heat Shock Protein 96 Mediates In Vitro Activation and In Vivo Expansion of Melanoma and Colon Carcinoma-Specific T Cells. J. Immunology, 171(7):3467-3474, 2003.

  14. Belli R, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, Gallino G, Piris A, Cattelan A, Lassari I, Carrabba M, Scita G, Santantonio C, Pilla L, Tragni G, Lombardo C, Arienti F, Marchianň A, Bertolini F, Cova A, Lamaj E, Ascani L, Camerini R, Corsi M, Cascinelli N, Lewis JJ, Srivastava PK, Parmiani G. Vaccination of metastatic melanoma patients with autologous Tumor-derived heat shock protein gp96-peptide complexes. J. Clinical Oncology, 20 (20): 4169-4180 , 2002.

  15. Binder RJ, Kumar A, Srivastava PK. Naturally formed or artificially reconstituted non-covalent a2-macroglobulin-peptide complexes elicit CD91-dependent cellular immunity. Cancer Immunity, Vol. 2 pg 16, 2002.

  16. Stebbing J, Gazzard B, Kim L, Portsmouth S, Wildfire A, Morlese J, Shaunak S, Nelson M, Bower M, Srivastava P, Gotch F, Patterson S. CD91, the heat shock protein receptor is up-regulated on HIV-1-infected "true" long term non-progressors. Blood, 101 (10), 4000-4004, 2003.

  17. Makki A, Weidt G, Blachere N, LeFrancois L, and Srivastava PK. Abrogation of tumore protection by immunization against a dominant tumor antigen. Cancer Immunity, Vol. 2, pg. 4, 2002

  18. Panjwani NN, Popova L, Srivastava PK. Heat shock proteins gp96 and hsp70 activate release of Nitric Oxide by antigen presenting cells. J. of Immunology, 168 (6), 2997-3003, 2002.

  19. Srivastava PK. Heat shock proteins in innate and adaptive immunity. Nature Reviews Immunology, Vol. 2, 185-194, 2002.

  20. Srivastava PK. Interaction of Heat shock proteins with peptides and antigen presenting cells : Chaperoning of the innate and adaptive immune responses. Annual Reviews of Immunology, Vol. 20, 395-425, 2002.

  21. Li Z, Menoret A, Srivastava PK. Roles of heat-shock proteins in antigen presentation and cross presentation. Current Opinions in Immunology, 14(1), 45-51, 2002.

  22. Binder, RJ, Karimeddini D, Srivastava PK. Adjuvanticity of a2-macroglobulin, an independent ligand for the heat shock protein receptor CD91. Journal of Immunology, 166: 4968-4972, 2001.

  23. Basu S, Binder RJ, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin, Immunity, 14, 303-313, 2001.

  24. Ménoret A, Li Z, Niswonger ML, Altmeyer A, Srivastava PK. An endoplasmic reticulum protein implicated in chaperoning peptides to major histocompatibility of class I is an aminopeptidase. Journal of Biological Chemistry, 276: 33313-33318, 2001.

  25. Somersan S, Larsson M, Fonteneau JF, Basu S, Srivastava PK, and Bhardwaj N. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J. of Immunology, 167: 4844-4852, 2001.

  26. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver maturation signal to dendritic cells and activate the NFkB pathway. International Immunology, 12 (11), 1539-1546, 2000.

  27. Binder RJ, Anderson KM, Basu S, Srivastava PK. Heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. Journal of Immunology - Cutting Edge, 165: 6029-6035, 2000.

  28. Srivastava PK. Immunotherapy of human cancer: lessons from mice. Nature Immunology,1 (5), 363-366, 2000.

  29. Binder RJ, Han DK, Srivastava PK. CD91 is a receptor for heat shock protein gp96. Nature Immunology, 1 (2), 151-155, 2000.

  30. Janetzki S, Polla D, Rosenhauer V, Lochs H, Srivastava PK. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 : A pilot study. Intl. Journal of Cancer , 88, 232-238, 2000.

  31. Chandawarkar RY, Wagh MS, Srivastava PK. The dual nature of specific immunological activity of tumor-derived gp96 preparations. J. Exp. Med., 189 (9): 1437-1442, 1999.

  32. Basu S, Srivastava PK. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity. J. Exp. Med. 189, (5): 797-802, 1999

  33. Srivastava PK, Ménoret A, Basu S, Binder R, McQuade K. Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world. Immunity (8): 657-665, 1998.

  34. Tamura Y, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of metastatic lung cancer by heat shock protein preparations. Science 78(5335): 117-120,1997.

  35. Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein - chaperoned peptides. Science 269, 1585-1588, 1995.

  36. Udono H, Srivastava PK. Relative immunogenicities of Heat Shock Proteins gp96, hsp90 and hsp70 against chemically induced tumors Journal of Immunology 152, 5398-5403, 1994.

  37. Udono H, Srivastava PK. Heat shock protein 70 - associated peptides elicit specific cancer immunity . J Exp. Medicine 178, 1391-1396, 1993.

  38. Maki, R.G., Old, L.J. and Srivastava, P.K. Human Homologue of Murine Tumor Rejection Antigen Gp96: Analysis of Regulatory and Coding regions and Relationship to Stress-Induced Proteins. Proc. Natl. Acad. Sci. USA 87 : 5658 - 5662, 1990.

  39. Srivastava, P.K. DeLeo, A.B. and Old, L.J. Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc. Natl. Acad. Sci., U.S.A. 83: 3407-3411, 1986.

  40. Srivastava, P.K. and Das, M.R. Serologically unique surface antigen of a rat hepatoma is also its tumor-associated transplantation antigen. Int. J. Cancer. 33: 417-422, 1984.


Laboratories | Ph.D. Program | Clinical Activities | News & Events | About CICID | Site Map | Home

UConn Health Center
Send comments or questions to: info@immunotherapy.uchc.edu
Phone: 860-679-4444 Fax: 860-679-7905

Center for Immunotherapy of Cancer and Infectious Diseases
University of Connecticut Health Center
263 Farmington Avenue
Farmington, Connecticut 06030-1601

Copyright 2001 University of Connecticut Health Center
Web site developed by Innovative Internet Marketing Solutions