ORLANDOHeat shock proteins (HSPs) purified from tumor cells carry the unique "antigenic fingerprint" of that tumor, and vaccination with tumor-derived HSPs induces specific tumor immunity, said Pramod K. Srivastava, PhD, professor of immunology and director of the University of Connecticut Cancer Center, Farmington.
Speaking at a symposium held in conjunction with the 2002 ASCO annual meeting, Dr. Srivastava explained that each tumor has a unique antigenic profile related to the accumulation of random mutations. With each division of a tumor cell, an estimated 6 to 60 random mutational changes occur, and because tumor cells are continually dividing, a vast number of mutations eventually accumulate. This results in a tumor cell population in which each cell has a unique antigenic profile.
Therefore, although several well-described specific tumor antigens exist, the complete characterization of the antigens associated with an individual tumor is not "practically knowable," he said, owing to the randomness of their generation. However, by isolating the HSPs from individual tumors, it is possible to capture the antigenic fingerprint of that specific tumor.
Heat shock proteins are present in every living cell and have been conserved throughout evolution, from bacteria through humans, Dr. Srivastava said. Collectively, HSPs constitute approximately 10% of the total intracellular protein content. Although the expression of HSPs is increased in response to heat shock, glucose deprivation, or other stresses, HSPs are present in abundant levels even under normal conditions.
Each HSP molecule serves as a chaperone for an individual peptide, and together the HSPs collect a heterogeneous assortment of peptides representative of the antigenic profile of each cell. An extraordinarily useful property of the HSPs, Dr. Srivastava said, is that although a given HSP may purify into a single band, there is actually a vast heterogeneity of chaperoned peptide sequences within this single band. "If, for example, you purify HSPs from a mouse leukemia, you will find leukemia antigens associated with the HSPs. In human melanomas, you’ll find antigenic peptides derived from the melanoma cells. So essentially, when you purify HSPs, you have an antigenic fingerprint," he said.
The HSPs also have immunogenic functions. They can chaperone peptides to antigen-presenting cells (APCs) in the lymph nodes. The APCs bind the HSPs and then re-present the HSP-chaperoned peptides on their MHC class I and II molecules. Interaction with HSPs also stimulates APCs to release cytokines.
Vaccines derived from HSPs can provide specific immunity against individual tumors, Dr. Srivastava said. He described an animal study in which, following surgery to remove pre-existing tumors, mice were vaccinated with HSPs derived from their individual tumors. The majority of vaccinated animals had long-term disease-free survival, whereas nonvaccinated mice died within a short time after surgery due to the persistence of micrometastatic disease.