T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity.

Abstract

A central problem in tumor immunology has been to explain how immunogenic tumors escape destruction by the immune defenses of their immunocompetent hosts. The results of studies performed during the past few years in this laboratory (reviewed in 1) support the hypothesis that certain tumors with tumorspecific, transplantation antigens avoid destruction by the immune response of their hosts by evoking the production of a population of suppressor T cells that functions to downregulate the immune response before enough effector T cells are generated to cause tumor regression . These published studies (2, 3) show that growth of the immunogenic tumors under investigation evokes the generation of an underlying state of concomitant immunity, which develops progressively between days 6 and 9 of tumor growth, and which is mediated by Ly-2 + effector T cells. After day 9, however, there is progressive loss of effector T cells, and this is temporarily associated with the progressive acquisition of Ly-1 +,2-suppressor T cells that are functionally defined by their ability to inhibit, on passive transfer, the expression of adoptive immunity against an established tumor in immunodepressed test recipients. It was postulated, on the basis of these and other results (1), that the loss of effector T cells results from negative regulation by tumor-induced suppressor T cells.However, other investigators have described the generation of a different type of suppressor T cell in mice bearing progressive immunogenic tumors (reviewed in 4). This second type of suppressor T cell displays the Ly1 -,2+, I-J' membrane phenotype, is generated at a very early stage of tumor growth, and is defined by its ability to suppress, on passive transfer, a delayed-type hypersensitivity (DTH)' reaction to tumor antigens in tumor-immune recipients. Because these suppressors of DTH are generated progressively during the first 6-7 d of tumor growth (5, 6), but are then progressively lost (6), it seems unlikely that they would exert a meaningful suppressor function in those situations where a tumor evokes the generation of a state of concomitant antitumor immunity that does not peak until day 9 of tumor growth, and does not undergo decay until after days 9-12.

Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

“…Because the majority of solid tumors are thought to express tumor-associated Ags (TAA), 2 it is believed that the induction of an effective anti-TAA immune response may enable the eradication of micrometastases. Studies in experimental models have indicated that TAA on many tumors are "concealed" from the immune system by two major mechanisms: 1) the tumor microenvironment and local cytokine milieu that often suppress immune function and may actively induce immune cell tolerance, anergy, and death (1-4); and 2) regulatory T cells (Treg) within the tumor and/or in the circulation that suppress the development of an anti-TAA (i.e., anti-tumor) immune response (5)(6)(7)(8).…”

“…These APC transport internalized TAA to draining lymph nodes where they present TAA peptides for the activation of tumor-specific cytotoxic and helper T cells at levels sufficient to overcome suppressive Treg activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). We have developed a novel method for achieving immune-mediated destruction of tumor lesions, recruitment of APC into the lesions, effective intratumoral targeting of TAA to recruited APC, and induction of a protective anti-tumor immune response by exploiting the naturally produced anti-Gal Ab.…”

Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity

“…This phenomenon has been deemed a mechanism for tumor metastasis (4 -6). In a series of elegant studies, it was proposed that concomitant tumor immunity represents a balance between tumor-induced CD8 effectors and suppressor T cells (7,8). However, after this proposal, there was no progress made in the area for two decades, as the existence of suppressor cells was in doubt.…”

T-cell epitope peptide vaccines

“…Cytokines such as IL-7 and IL-21 are key molecules that provide necessary signals for T-cell proliferation [115,116]. LDCy may also enhance immune responses by preferentially targeting CD4 + regulatory T-cells, which have been shown to be inhibitory towards CTL and HTL responses against self-antigens such as TAA [117][118][119][120][121][122][123].…”