Role of immune defenses in lung cancer therapy
Initial Award Abstract
1. Cancer can result from failure of our immune system to reject tumors.
Cancer represents a normal and continuous biological process that is observed in all biological organisms, including plants. However, normal individual cancer cells are continuously eliminated by certain cells of our immune system. These cells are called T lymphocytes and represent a subset of our white blood cells. Normally, T cells are circulating in all compartments of our body and they are looking for the presence of invaders, such as bacteria and viruses, or for the presence of abnormal cells, such as cancer cells. This process, referred to as immune surveillance, insures a continuous protection against infection and cancer. However, for reasons that remain obscure to immunologists, the immune surveillance sometimes fails and cancer cells can proliferate and invade certain tissues or organs and form tumors; this phenomenon is known as immune escape.
2. The p53 gene-derived protein is an essential element of lung cancer
The use of tobacco is associated with increased risk for lung cancer. Mutation in the p53 gene (and related changes in the production of its associated protein) is the most frequently reported gene alteration in human lung cancer; it is also associated with resistance to treatment such as radiotherapy and chemotherapy.
Normally, proteins such as cancer-associated proteins are like flags presented at the surface of tumors alerting the immune system that something abnormal is happening. These proteins are presented to our immune system, not as a whole, but in the form of fragments. In our laboratory, we have performed a study which has shown that, during cancer, an immune response to p53 protein can be detected. Moreover, we have already identified to which portions (protein fragments) of p53 protein the immune response is directed. Finally, we have accumulated some evidence that indicates that the immune response to p53 is a dynamic process that changes during the course of cancer.
This initial work gives us the unique opportunity to address the question of the immune escape of cancer cells. Our project is to use the model of p53 in lung cancer to:
1) analyze immune responses to p53 in cancer. We will determine why the immune system, although it recognizes 2 fragments of p53 on cancer cells, does not eliminate tumor-forming cells. To address this question, we will monitor the immune response to each of the fragments of p53 we previously identified at different stages of tumor formation.
2) design a cancer vaccine based on p53. We will immunize mice with each of the previously identified p53 fragments, either prior or during tumor formation. Then, we will test the effects of such treatments on the immune response to p53 molecule, the ability of immune cells to recognize cancer cells and prevent the formation or the progression of lung tumors. |
Objectives and specific aims of the project:
Mutation of the P53 gene is most frequent gene alteration in human lung cancer. Once P53 is mutated, cancer cells proliferate, form tumors and metastasis and become often resistant to radio- and chemo-therapies. We and others have previously provided direct evidence showing that, during tumorigenesis, anti-tumor immune response is elicited. However, for reasons which remain ill defined, this immune response is not efficient, enough to achieve tumor eradication. We hypothesized that cancer cells do not escape immune surveillance but elicit a type of immune response which is protective to the tumor. In this scenario, cancer cells would-be considered as autologous cells and subsequently actively tolerated by the host thereby promoting tumor progression. Our main objective: was to determine: 1} whether P53 serves as a target antigen for T cells during tumorigenesis, 2) which precise fragments of P53 induce T cell responses, 3) the precise nature (phenotype: type 1 vs. type 2) of the immune response to P53 determinants at different stages of tumor formation.Findings:
We have performed a thorough analysis of the immune response to P53 in mice during tumorigenesis as well as in mice immunized. with P53 protein and P53 peptides. We systematically mapped all the determinants on P53 that are presented to T lymphocytes during the course of tumorigenesis. In addition, we generated T cell lines directed .toward each of the identified P53 determinants and used these CD4+ T cells in in vitro assays. We identifed 3 P53 determinants: 2 (P53.1 and P53.4) were dominant as they were naturally processed and presented during tumor formation and P53.3 which contains a cryptic epitope which is not presented although it binds to major histocompatibility complex protein of the host (BALE/c H-2d). Interestingly, P53.2 apparently represents a determinant which is regularly presented on "normal" non-tumor cells and had induced self-tolerance. Next, we observed that while P53.1 is presented during the initial phase of tumorigenesis, as the tumor progresses, P53.4 becomes predominant. Most importantly, this response is characterized by the overwhelming production of IL-5 lymphokine by T cells suggesting that indeed this response may be protective toward the tumor. Late gIFN production to the tumor is apparently not sufficient to prevent further metastasis. Further supporting our hyspothesis, we observed that vaccination with this peptide exarcerbates tumongenesis and accelerate tumor formation. In conclusion, we have identified two types of determinants on P53 which elicits immune responses to the tumor; vaccination with type 1 or tolerance to type 2 determinants should be utilized to stengthen anti-tumor immunity. |