Principles of tumor immunosurveillance and implications for immunotherapy

Abstract

Although antigen loss variants, major histocompatibility ( MHC ) class I down -regulation, or the expression of inhibitory molecules may explain the failure of immunosurveillance against some tumors, this seems not to apply for many other solid peripheral or lymphohematopoietic tumors. Why then is immunosurveillance so ineffective and can it be improved? This review focuses on one important aspect of tumor immunity, namely the relevance of antigen dose and localization. Immune responses in vivo are induced in organized lymphoid tissues, i.e., in lymph nodes and spleen. The antigen dose that reaches secondary lymphoid organs over time is a crucial parameter that drives antiviral and antitumoral immune responses. Tumors use various strategies to prevent efficient presentation of their antigens in lymphoid organs. A major obstacle to the induction of an endogenous tumor -specific cytotoxic T lymphocyte ( CTL ) response is the inefficient presentation of tumor antigen on MHC class I molecules of professional antigenpresenting cells. Peripheral solid tumors that develop outside lymphoid organs are, therefore, often ignored by the immune system. In other situations, tumors -especially of lymphohematopoietic origin -may tolerize specific CTLs. Understanding tumor immunosurveillance is key to the design of efficient antitumor vaccines. Attempts to improve immunity to tumors include vaccination strategies to ( a ) provide the tumor antigen to secondary lymphoid organs using recombinant viruses or dendritic cells as carriers, ( b ) express costimulatory signals on tumor cells, or ( c ) improve the efficiency of cross -priming.

Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2

“…T cells play an important role in immunological surveillance against cancer cells as well as in tumor destruction (20). Successful identification of a number of tumor Ags from both human and murine melanomas has allowed the development of Ag-specific cancer vaccines (21).…”

Antigen Distribution Drives Programmed Antitumor CD8 Cell Migration and Determines Its Efficiency

“…Other studies (16) suggest that high Ag doses in SLOs lead to the development of T cell tolerance. Accordingly, we examined the susceptibility to cell death of Ag-specific CD8 T cells in the LNs and spleen upon TCR re-engagement with high doses of Ag: we used annexin V staining to analyze the death rate and found that many more CD8 cells restimulated with EG7 died within 24 h (39 and 30% of the CD8 cells isolated, respectively, from the LNs and spleen) than did those restimulated with EL-4 (12 and 16%) (Fig.…”

“…Furthermore, diffusely invading systemic tumors delete CTLs. Thus, it is the Ag dose in the SLOs that determines whether T cells remain ignorant, are activated, or become tolerized (15,16). Precise definitions of the kinetics of CD8 antitumor activation, proliferation, migration, and differentiation are crucial in improving the efficiency of tumor rejection.…”

Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing

“…Antitumor cytotoxic T-lymphocytes (CTLs) are central to immunotherapeutic anticancer strategies (1)(2)(3)(4)(5). Tumorspecific CTLs can be induced by various immunotherapeutic strategies (reviewed in 3), and tumor-infiltrating lymphocytes are found "naturally" in tumors (6).…”