The promise of cancer immunotherapy is based upon the exquisite specificity of the immune system, through which a potent machinery can eliminate targeted cells. However, despite some notable examples of success, progress in developing this form of cancer therapy has fallen short of expectations. Major insights explaining the limitations of T cell-based cancer immunotherapies have come from the discovery of inhibitory co-receptors or pathways termed immune checkpoints, which restrain T cell functions in normal physiologic settings as well as in the context of neoplastic disease. Recent evidence suggests that tumors may """"""""usurp"""""""" immunological checkpoint mechanisms to create a barrier against antitumor immune responses - including endogenous responses and those induced by immunotherapies such as cancer vaccines. Animal cancer models demonstrate that blocking the interaction of inhibitory molecules on tumor cells with their co-receptors on tumor-specific T cells can """"""""release the brakes"""""""" on antitumor immunity and cause tumor regression. Thus, checkpoint inhibition, applied alone or in combination with vaccines, represents an important new therapeutic approach for enhancing antitumor immunity. One of the most interesting inhibitory co-receptors is PD-1, that is induced on activated T cells and down-modulates critical functions in both CD4+ (""""""""helper"""""""") and CD8+ (""""""""killer"""""""") subsets. The major ligand for PD-1 is B7-H1 (PDL1), a B7 family member normally expressed by several leukocyte subsets upon activation, and aberrantly expressed in many human cancers. These findings, highlighting multiple mechanisms by which PD-1/B7-H1 interactions may inhibit antitumor immunity, have provided a rationale for clinical trials in cancer patients using fully human antibodies blocking PD-1 or B7-H1. Notably, objective tumor regressions were observed in the first phase I trial of PD-1 blockade in patients with advanced treatment-refractory metastatic solid tumors. It is now critically important to better understand the regulation and function of PD-1 and B7-H1, and to discern the effects of PD-1/B7-H1 blockade on antitumor immunity. In current proposal, we will test hypothesis that modulation of B7-H1/PD-1 inhibitory pathway could vastly enhance efficacy of cancer immunotherapy by improving tumor microenvironment and protecting ongoing T cell activity. The current proposal integrates basic and clinical science, and will use animal models and human in vitro systems to achieve the following aims: 1) To define mechanisms regulating B7-H1 expression by tumor cells and other cell types in the tumor microenvironment;2) To characterize factors influencing PD-1 expression by T cells, particularly in the context of vaccine-induced stimulation;and 3) To characterize immunological mechanisms underlying the clinical effects of B7-H1/PD-1 blockade in cancer therapy. Taken together, results from these studies will enable the rational clinical development of PD-1/B7-H1 blockade, alone or in combinatorial regimens, in cancer therapy.
Although remarkable progress has been made on a scientific level in understanding regulatory processes governing the activity of the immune system against cancer, the clinical application of these findings to develop effective cancer therapies will require a more detailed knowledge of the molecules and pathways involved. Our objectives are 1) to elucidate how interactions of the immune regulatory molecules B7-H1, expressed by cancer cells, and PD-1, expressed by activated antitumor T lymphocytes, support cancer progression;and 2) to use this knowledge to develop effective cancer immunotherapies based on blockade of B7-H1/PD-1 ligation.
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|Cottrell, Tricia R; Taube, Janis M (2018) PD-L1 and Emerging Biomarkers in Immune Checkpoint Blockade Therapy. Cancer J 24:41-46|
|Forde, Patrick M; Chaft, Jamie E; Smith, Kellie N et al. (2018) Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 378:1976-1986|
|Taube, Janis M; Galon, Jérôme; Sholl, Lynette M et al. (2018) Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 31:214-234|
|Cottrell, Tricia R; Duong, Anh T; Gocke, Christopher D et al. (2018) PD-L1 expression in inflammatory myofibroblastic tumors. Mod Pathol 31:1155-1163|
|Giraldo, Nicolas A; Nguyen, Peter; Engle, Elizabeth L et al. (2018) Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab. J Immunother Cancer 6:99|
|Sunshine, Joel C; Nguyen, Peter L; Kaunitz, Genevieve J et al. (2017) PD-L1 Expression in Melanoma: A Quantitative Immunohistochemical Antibody Comparison. Clin Cancer Res 23:4938-4944|
|Yanik, Elizabeth L; Kaunitz, Genevieve J; Cottrell, Tricia R et al. (2017) Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma: Implications for Immunotherapy. JAMA Oncol 3:974-978|
|Kaunitz, Genevieve J; Loss, Manisha; Rizvi, Hira et al. (2017) Cutaneous Eruptions in Patients Receiving Immune Checkpoint Blockade: Clinicopathologic Analysis of the Nonlichenoid Histologic Pattern. Am J Surg Pathol 41:1381-1389|
|Kaunitz, Genevieve J; Cottrell, Tricia R; Lilo, Mohammed et al. (2017) Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest 97:1063-1071|
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