Tumor infiltrating lymphocytes (TILs): Lessons learned in 30 years of study

The interplay between tumor development and the host immune system, as well as the impact of the immune system on the tumor's metastatic potential is incompletely defined. Almost 30 years ago, the identification of tumor infiltrating lymphocytes was reported, and represented great hope in cancer treatment. At that time, it was thought that patients whose tumors had high numbers of tumor infiltrating lymphocytes had a good prognosis, while patients with few or no tumor infiltrating lymphocytes had a poor prognosis. Work published since that seminal report has indicated that this viewpoint is overly simplistic. While infiltration of the tumor with lymphocytes may be one factor associated with a positive outcome, the milieu required for optimal functioning of the immune system is also defined by the presence of potent antigen presenting cells, immunostimulatory cytokines, and optimal surface molecule expression by both the tumor cells and the infiltrating lymphocytes. The complexities of these interactions are just beginning to be defined; a further difficulty that must be addressed in the development of cancer immunotherapy regimens is that various forms of cancer appear to have different immune system requirements. Failure of the host to achieve the optimal tumor microenvironment severely compromises the ability of the host to control tumor growth and metastases. Animal models of cancer, imperfect as they are, can provide investigators with model systems for manipulating the immune parameters of the tumor site within the host to determine its effect on disease outcome. While mouse models cannot fully mimic the processes observed in humans because of differences in surface molecule expression and signaling pathways between the species, they do provide investigators with a means to examine the mechanisms involved following immunotherapy. This review will discuss some of the immune parameters studied in tumor infiltrating lymphocytes and how they have been associated with patient prognosis.