Immunology Graduate Group

Lionel A. Manson, Ph.D.
Department of Biology

Office Phone:  (215) 898-5599
Email:  lmanson@sas.upenn.edu

Education:
B.A., Biological Chemistry, University of Toronto
M.A., Biological Chemistry, University of Toronto
Ph.D., Biological Chemistry, Washington University
Post Doctoral Fellow, Western Reserve University

Research Interests

Immunological responses during progressive tumor growth; MMTV.

Research Summary

A major unanswered question in tumor immunology is what are the characteristics of the immune responses of a normal host to a spontaneous, progressively-growing tumor.

Our observations have been recently summarized under the title of the oncotope hypothesis. Briefly, an oncotope is a tumor-unique epitope that is expressed on the surface membrane of a malignant cell. Oncotopes are immunogenic in their host of origin. An initial immune response is a 
T-independent B cell response; B1 B cells interact with tumor cells, and anti-oncotope IgM is produced locally at the tumor site. All of the antibody is immediately bound to the tumor cells, and tumor cell growth continues unimpeded. This anti-oncotope IgM coating prevents the cytolysis of the tumor cells by T-killer cells which develop later at the tumor site, i.e. the tumor cells become killer cell resistant. Free antibody is not found in the sera or tissue fluids of the tumor-bearing host. Thus the tumor-bearing host is fully immune to the tumor it is bearing at the time of tumor diagnosis.

A number of questions associated with this approach are under investigation at present: 1) monoclonal antibodies are currently being made that specifically react with the oncotopes of a number of tumor; these will be useful tools for describing the size of the universe of oncotopes among tumor - some surprises are already evident in the cross-reactivities that have been observed

2) such monoclonal antibodies will be useful in characterizing biochemically, the gene products that express the oncotopes, and in cloning the genes that control the oncotopes;

3) such monoclonal antibodies will be essential in designing immunotherapeutic approaches to inducing tumors to regress.

The killer cell activity found in the peritoneal cavity of a tumor-bearing mouse (ascites) and in the spleens of immunized mice are shown. 1) Peritoneal killer cells are MHC-unrestricted; they kill tissue culture grown targets (EL4, P815Y) but do not kill tumor cells that have grown inside the animal for 2 weeks (EL4*, P815y*) 2) Spleen killer cells from immunized animals syngeneic for the tumor are MHC-restricted; they do not kill EL4* or P815y* 3) Spleen killer cells from F1 hybrid immunized animals kill both tumors, but do not kill EL4* or P815y* Conclusion ­ immunogenic tumor cells become killer cell resistant and thus grow progressively in the face of a complete immune response developed against the tumor.

FACS Studies of Growing Tumors In the figure are shown FACS scans of EL4 grown in culture (A) and grown in a mouse for 16 days(B), also scans of P815-X2, a non-immunogenic tumor grown in culture (C) and grown in an animal for 2 weeks (D). Both in vivo-grown tumor are covered with IgM, and it is proposed that the IgM coating make the tumors killer cell resistant.

 

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