Tumor Escape And Future Approaches To Cancer Immunotherapy

Recent progress in tumor immunology has led to novel insights regarding the functions and interactions of immune cells (T, B, NK, M and DC) and the molecules expressed on these cells, which are linked to the development and efficacy of TA-specific immune responses. In addition, a better understanding of the molecular signals and mechanisms involved in the generation of productive immune responses in general has focused attention on those molecular events that occur or do not occur in the tumor microenvironment. The realization that immune cells undergo apoptosis in tumors has led to a search for the mechanism(s) responsible for this death and was instrumental in identifying the TNF family of receptors and ligands as instrumental in mediating tumor-induced apoptosis (165-167). This realization was prefaced by the recognition of the Fas/FasL pathway and its role in maintaining the immune privilege at sites such as the anterior chamber of the eye, the brain, the testis or the thyroid gland (168). The notion that tumors might also be able to protect themselves from immune effector cells by inducing their death was both appealing and supported by the extensive evidence that these effector cells are dysfunctional in the tumor microenvironment (21,23, Table 1). It also provided a reasonable explanation for the noted limited success of adoptive immunotherapies employing activated effector cells in patients with cancer (53). However, it has now become necessary to convincingly demonstrate that the newly identified mechanisms leading to apoptosis of immune cells apply to tumor-effector cell interactions. If immune effector cells die in the tumor, and if the rate of their demise exceeds that of survival, then it might be surmised that tumor-induced apoptosis of immune cells might be an important prognostic parameter. This hypothesis has to be tested. The potential ability of immunotherapies to protect effector cells from apoptosis might be related to the clinical response of patients, and this hypothesis can also be formally examined. The question of how to best protect immune cells from premature tumor-induced apoptosis becomes an essential, but so far inadequately explored, goal of cancer immunotherapy.

Extensive immunization trials are on-going worldwide in patients with breast, colon, renal cell, ovarian and prostate carcinomas as well as melanoma and other malignancies. These clinical trials, largely initiated in patients with advanced metastatic disease, have been able to induce clinical responses in not more than 20% of patients. They are unlikely to yield the desired results, if only a proportion of the immunization-induced, TA-specific effector cells survive in vivo. Moreover, if a proportion of specific T cells or DC are preferentially killed, and if the level of apoptosis exceeds that of effector cell influx into the tumor or their generation within the secondary lymphoid sites, the immunization strategies (as currently applied) may prove ineffective. Likewise, it may be counterproductive to generate TA-specific effector cells in a situation where the tumor is resistant to that type of immune cell, i.e., poised to escape specific immune interventions. To avoid additional disappointments in the clinic, it will be necessary to combine immunization strategies with therapies providing: a) protection of T-cells from tumor-induced apoptosis and b) improved recognition of tumor cells (by interfering with their mechanisms of immune escape). Preliminary experiments suggest that effectively (Type-1) polarized DC as well as survival cytokines can protect TA-specific immune effector cells from apoptosis in the tumor microenvironment and, at the same time, alter expression of key components of the antigen processing machinery in the tumor, thus making tumor cells susceptible to immune attack. Therefore, the rationale exists for the implementation of this approach with the objective of defining the molecular and cellular signals responsible for the observed dysfunction of immune cells and/or for tumor escape. The resulting information is expected to be useful to optimize studies to investigate in preclinical in vitro models as well as in clinical trials the possible beneficial effects of DC and/or cytokine administration on protection of immune cells from apoptosis.

A better understanding of the fate of anti-tumor effector cells generated in vivo or those that are adoptively transferred into patients with advanced malignancies is of critical importance to the optimization of effective cancer immunotherapy in the future. Although several mechanisms that could be responsible for the development of immune cell dysfunction in tumor-bearing hosts have been identified, none can systematically account for the range and magnitude of dysfunction and immune cell death observed in patients with cancer (58,67,156,169). Many unanswered questions remain, and research is critically needed in order to distinguish between those mechanisms that might favor tumor escape through modification leading to greater resistance of tumor cells vs. those attributable to effects the tumor exerts (directly or indirectly) on immune effector cells. With new insights into proliferation and death of immune effector cells in the tumor microenvironment (170), cytokine and growth factor biology (171,172), the role of DC in antigen cross-presentation (32), regulation of target-cell killing (44,173) and mechanisms underlying the apoptosis of immune cells (21,23), it has been possible to formulate a series of testable hypotheses regarding the nature of the mechanisms that mediate tumor escape or tumor-induced cell death. Further, novel therapeutic strategies that could prevent tumor evasion and protect immune effector cells from apoptosis in the tumor microenvironment need to be tested for efficacy in changing the fate of TA-specific immune effector cells and thus improving outcome.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment