Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract


Cancer immune surveillance is considered to be an important host protection process to inhibit carcinogenesis and to maintain cellular homeostasis. In the interaction of host and tumour cells, three essential phases have been proposed: elimination, equilibrium and escape, which are designated the ‘three E’s'. Several immune effector cells and secreted cytokines play a critical role in pursuing each process. Nascent transformed cells can initially be eliminated by an innate immune response such as by natural killer cells. During tumour progression, even though an adaptive immune response can be provoked by antigen-specific T cells, immune selection produces tumour cell variants that lose major histocompatibility complex class I and II antigens and decreases amounts of tumour antigens in the equilibrium phase. Furthermore, tumour-derived soluble factors facilitate the escape from immune attack, allowing progression and metastasis. In this review, the central roles of effector cells and cytokines in tumour immunity, and the escape mechanisms of tumour cells during tumour progression are discussed.

Keywords: cancer, immune escape, immune surveillance, immunoediting







https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2265921/

Abstract


Many peripheral solid tumors such as sarcomas and carcinomas express tumor-specific antigens that can serve as targets for immune effector T cells. Nevertheless, overall immune surveillance against such tumors seems relatively inefficient. We studied immune surveillance against a s.c. sarcoma expressing a characterized viral tumor antigen. Surprisingly, the tumor cells were capable of inducing a protective cytotoxic T cell response if transferred as a single-cell suspension. However, if they were transplanted as small tumor pieces, tumors readily grew. Tumor growth correlated strictly with (i) failure of tumor cells to reach the draining lymph nodes and (ii) absence of primed cytotoxic T cells. Cytotoxic T cells were not tolerant or deleted because a tumor antigen-specific cytotoxic T cell response was readily induced in lymphoid tissue by immunization with virus or with tumor cells even in the presence of large tumors. Established tumors were rejected by vaccine-induced effector T cells if effector T cells were maintained by prolonged or repetitive vaccination, but not by single-dose vaccination. Thus, in addition to several other tumor-promoting parameters, some antigenic peripheral sarcomas—and probably carcinomas—may grow not because they anergize or tolerize tumor-specific T cells, but because such tumors are immunologically dealt with as if they were in a so-called immunologically privileged site and are ignored for too long.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC26766/

DISCUSSION

Our experiments illustrate in a model situation the following simple concept: antigens that do not enter organized lymphoid tissues at sufficient levels do not induce an efficient CTL response; thus many strictly peripherally expressed self antigens (33) and also highly antigenic and successfully growing peripheral tumors are ignored by the immune system. If the same so far ignored antigen enters lymphoid organs, a T cell response is induced. A late, weak, or time-limited immune response does not suffice to cause tumor rejection, whereas vigorous and sustained T cell responses can achieve complete rejection. The overall rejection success therefore depends on the relative kinetics of tumor cell numbers (or tumor size, influenced by growth rate and several other tumor parameters) vs. kinetics and relative numbers of effector T cells over time. The importance of this balance is demonstrated here by the finding that postexposure vaccination was inefficient after a single vaccination but was able to control the small tumors completely with multiple vaccinations (Fig. ​(Fig.55 d–f).

Thus, three situations may be distinguished that may have clinical parallels: (i) A low dose of single tumor cells or small s.c. solid tumors may grow locally as a consequence of none or too few tumor cells reaching draining lymph nodes during early tumor development; these tumors are therefore ignored immunologically and neither induce nor tolerize T cells. The surprisingly successful formation of tumor by small but not by great numbers of experimental tumor cells injected s.c. had been reported earlier and has been described as “sneaking through” (1). (ii) Sufficient numbers of cells from many initially growing tumors may eventually reach draining lymph nodes, induce an efficient CTL response, and therefore be rejected; such tumors will usually not become clinically apparent unless this immune response comes too late (see ref. 3), MHC class I or tumor antigens are modulated, fast replication rates develop so that tumors outrun CTL responses, or other escape mechanisms evolve. (iii) Great numbers of experimental tumor cells will grow, as in clinically manifest tumors that have already reached a large size, despite induction of effector cells because the relative low numbers of antitumor-specific T cells are too inefficient to control large numbers of peripheral tumor cells (29, 31). This latter situation may also be found in human sarcomas and carcinomas that metastasize “relatively” early and where specific tumor-infiltrating lymphocytes (34) or even lymphatic metastasis may be found; effector T cells are apparently induced, but too late — or the T cell response is too weak — to control/reject the established tumor masses. Our example studied in Fig. ​Fig.55 d–f impressively illustrates the demanding requirements: The few slightly (<5-fold) larger tumors tended to resist complete rejection even by repetitive vaccinations. Drastic reduction of tumor cell load, e.g. by surgery, and enhancement of T cell responses by expansion in vitro, or continued boosting in vivo by appropriate postexposure vaccination as shown here, may reverse an unfavorable balance. Overall, the present experiments illustrate the possibility that strictly peripheral sarcomas (or probably also carcinomas) grow because such tumors stay outside the immune system and are therefore immunologically ignored for too long.

It is a very good highlighting Debbie, it confirms our long standing conviction that it is beneficial for the patient to reduce the tumor load either by the resection or an ablation to enable the better treatment response.