Immunotherapy in the treatment of cancer has made major strides during the last decade. For instance, antibody-mediated immunotherapy has been applied since 1997 when the first FDA approved monoclonal antibody for cancer treatment, rituximab, was used to treat patients with B-NHL. Many other monoclonal antibodies directed against cell surface tumor associated antigens were developed and many of those are currently being used for the treatment of several tumor types with significant success. In addition to antibody-mediated immunotherapy, several strategies have been developed to generate antitumor cell-mediated cytotoxic cells with great success. However, the clinical response in the presence of a significant antitumor cytotoxic response still remains very poor. Several underlying mechanisms have been proposed for the poor clinical response including tumor cell modification and secretion of suppressor factors as well as the tumor microenvironment that participates in preventing killer cells to either interact and/or kill corresponding tumor cells. An important mechanism that has come to the attention of investigators deal with tumor cell development of mechanisms to resist killing by both cytotoxic cells and antibody-mediated cytotoxicity. Such mechanisms of immune resistance may account for the poor correlation between the presence of antitumor cytotoxic antibody or effector cells and the poor clinical response. Tumor cell development of resistance to killing is an important mechanism for tumor escape from immune surveillance. Several representative mechanisms have been described in this review which illustrate how tumor cells can resist killing by cytotoxic immunotherapeutic approaches. A better understanding of the molecular, biochemical, and genetic mechanisms that regulate immune resistance should provide a better understanding as well as develop novel approaches for therapeutic interventions to reverse resistance. Studies have demonstrated that interference with resistant factors in the tumor cells by a variety of sensitizing agents can reverse immune resistance. Such studies suggest that reversal of immune resistance may occur by combination treatment of immunosensitizing agents and immunotherapy. Thus, it may be possible in the presence of antitumor cytotoxic immunotherapy that the combination treatment in patients with sensitizing agents should alter the tumor resistant phenotype of the tumor cells and the patients can respond successfully to immunotherapy. In addition, the tumor microenvironment should not be neglected, as other factors in the microenvironment may still prevent cell killing due to blocking factors or factors that act on the cytotoxic lymphocytes. Here again one has to devise novel intervention approaches to counteract these factors. Hence, we may face novel combinations of therapeutic approaches that are complex and multi-targeted, namely sensitizing agents on the tumor cells, agents that potentiate the interaction of cyto-toxic cells with tumor cells in the microenvironment and agents that potentiate and activate the cytotoxic cells.
Acknowledgements I acknowledge the Jonsson Comprehensive Cancer Center for their valuable contribution. In addition, I acknowledge the various individuals that have contributed in the studies described: Ali Jazirehi, Ph.D.; Mario I. Vega, Ph.D.; Sara Huerta-Yepez, Ph.D.; Stavroula Baritaki, Ph.D.; Kazuo Umezawa, Ph.D.; and Eriko Suzuki. The author also acknowledges the assistance of Maggie Yang, Alina Katsman, and Amy Wu for the preparation of this manuscript.
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