T cell-mediated immunosuppression as an obstacle to adoptive immunotherapy of the P815 mastocytoma and its metastases.

Abstract

The numerous reports (1) showing that suppressor T cells are generated in response to growth of immunogenic tumors serve to provide an explanation for the paradoxical growth of these tumors in their immunocompetent syngeneic hosts. A recent publication (2) from this laboratory revealed, for example, that progressive growth of a transplantable murine tumor, the Meth A fibrosarcoma, results in the generation in the host of a T cell-mediated state of immunosuppression that prevents the regression of this tumor by passively transferred, tumor-sensitized T cells from immune donors. The presence of suppressor T cells in the tumor-bearing host was revealed in two ways: first, by showing that in order to demonstrate adoptive T cell-mediated regression of established tumors, it was necessary to use tumor-bearing recipients that had been made T cell deficient by thymectomy and gamma irradiation; second, by demonstrating that adoptive T cell-mediated regression of tumors in these T celldeficient recipients could be inhibited by prior infusion of splenic T cells from T cellintact, tumor-bearing donors. It was concluded that the failure of passively transferred, sensitized T cells to cause tumor regression in T cell-intact mice was caused by the presence in these mice of a tumor-induced state of T cell-mediated immunosuppression.The main purpose of this paper is to show that a strikingly similar mechanism of immunosuppression is generated in response to growth of the P815 mastocytoma. It will show, in addition, that passive transfer of sensitized T cells not only causes complete regression of the primary tumor but also causes the destruction of tumor metastases. Materials and MethodsMice. B6D2 (C57BL/6 × DBA/2), F1, CB6 (BALB/c × C57BL/6)F1, DBA/2, and BALB/c mice of either sex were used when they were between 8 and 12 wk of age. They were supplied by the Trudeau Institute Animal Breeding Facility.

Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

“…They show that it is only in the former that intravenously infused immune T cells are able to give rise to the production of an adequate number of cytolytic effector T cells. On the basis of results of previous studies (3,4), which showed normal tumor bearers possess T cells that can suppress the expression of adoptive immunity in TXB recipients, it was postulated that failure of passively transferred immune T ceils to cause tumor regression and give rise to the generation of an adequate number of cytolytic T cells in normal tumor-bearing recipients is due to the presence in these recipients of suppressor T cells. This was investigated by determining whether spleen cells from donors with established P815 tumors are capable, on passive transfer, of inhibiting the generation of cytolytic T cells in T cell-deficient tumor-bearing recipients of immune spleen cells.…”

“…The need for T cell-deficient tumor-bearing recipients to demonstrate successful adoptive immunotherapy suggested the existence in normal tumor bearers ofa T cell-dependent mechanism that prevents intravenously infused sensitized T cells from expressing their antitumor function. Evidence that this obstacle to adoptive immunotherapy is a tumor-induced, T cell-mediated mechanism of immunosuppression was supplied by the demonstration (3,4) that the passive transfer of splenic T cells from normal tumor bearers prevents passively transferred tumor-sensitized T cells from causing tumors to regress in T cell-deficient recipients. It was hypothesized, on the basis of this and other evidence (5) that the growth of an immunogenic tumor results in the generation of a state of T cell-mediated immunosuppression that functions to "down-regulate" a preceding concomitant immune response.…”

Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation

“…BALB/c TCR tg ("6.5") mice expressing a TCR specific for amino acids 110 to 120 of influenza hemagglutinin (HA) were a generous gift from Dr H. von Boehmer (Dana-Farber Cancer Institute, Boston, MA). 14 6.5 mice on a Thy1.1 ϩ/ϩ , Thy1.1 ϩ /Thy1.2 ϩ , or Rag2 Ϫ/Ϫ background were used in experiments where indicated. Experiments were conducted in accordance with protocols approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine.…”

“…[5][6][7][8][9] Indeed, we previously reported the paradoxical observation that mice with established B-cell lymphoma that underwent transplantation with marrow and lymphocytes from syngeneic tumor-bearing donors had superior progression-free survival to identical cohorts receiving grafts from non-tumorbearing donors. Mature postthymic T cells from the tumor-bearing donors were an essential component of the graft in mediating this effect.…”

“…19 Since that time, considerable attention has been given to the antitumor properties associated with infusion of T cells into lymphopenic hosts. [5][6][7][8][9] In this setting, the increased availability of cytokines such as IL-7 and IL-15 that govern lymphocyte homeostasis, as well as access to APCs that provide low-level TCR stimulation, both contribute to proliferation and expansion. 20,21 Several lines of evidence suggest that the mechanisms responsible for maintaining peripheral tolerance are altered during this "nonequilibrium" phase.…”