Multiple factors in the cancer microenvironment down-regulate tumor immunity and promote tumor progression. In melanoma, one of the dominant mechanisms is the induction of co-inhibitory receptors on tumor-specific T cells and expression of corresponding co-inhibitory ligands by tumor or other cells within tumor stroma, leading to complete or partial loss of T-cell effector functions. Amplified co-inhibitory interactions in the cancer microenvironment impede not only immune tumor surveillance, but also therapeutic immune interventions that may explain the failure of approaches aimed at stimulation of T cells, including tumor antigen-based vaccination and T cell stimulatory cytokines. A prime example of the co-inhibitory interactions is the B7-H1 (PD-L1)/PD-1 pathway. Early studies from our and other laboratories demonstrate a critical role of this pathway in the evasion of cancer immunity, and blockade of this pathway enhances ongoing immune responses against tumors. Recent phase I clinical trials conducted using a fully human antibody to PD-1 demonstrated durable objective (partial and complete) responses in 33% of pretreated metastatic melanoma patients (n=46). Collectively, these studies support B7-H1 as an important co-inhibitory molecule in the down-regulation of immune responses in the melanoma microenvironment and blockade of the B7-H1/PD-1 pathway as one of the most promising approaches for the treatment of melanoma. Project 2 will extend these laboratory and clinical findings in three directions;
The specific aims are:
Aim 1 : to assess the association between B7-H1/PD-1 expression in human melanoma microenvironment with clinical response to anti-PD-1 therapy;
Aim 2 : to study effector mechanisms of the B7-H1/PD-1 blockade in augmenting anti-melanoma immunity and in melanoma regression;
and Aim 3 : to maximize melanoma therapeutic immunity by mechanism-based combinatory approaches. Based on our finding that B7-H1 expression by melanoma is directly and extensively up-regulated by interferons, the combination of B7-H1/PD-1 blockade will be tested with IL-2 and interferon-a 2b, and with selective mutant BRAF inhibitors, which promote tumor T-cell infiltration. Our studies should have direct impact for current development of B7-H1/PD-1 blockade as a novel and promising approach for melanoma therapy.

Public Health Relevance

This proposal is based on exciting findings that the blockade of B7-H1/PD-1 interaction by an antibody can vastly augment immune responses, and produces clinical regression of advanced and metastatic melanoma in patients. The studies will identify potential predictive biomarkers for the patients who are most likely to respond to therapy, and will provide novel approaches to increase treatment efficacy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Kluger, Harriet M; Zito, Christopher R; Turcu, Gabriela et al. (2017) PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clin Cancer Res 23:4270-4279
Cyrenne, Benoit M; Lewis, Julia M; Weed, Jason G et al. (2017) Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients. Blood 130:2073-2083
Weed, Jason; Gibson, Juliet; Lewis, Julia et al. (2017) FISH Panel for Leukemic CTCL. J Invest Dermatol 137:751-753
Lazova, Rossitza; Pornputtapong, Natapol; Halaban, Ruth et al. (2017) Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas. Mod Pathol 30:640-649
Zhang, Yanchang; Cartmel, Brenda; Choy, Courtney C et al. (2017) Body mass index, height and early-onset basal cell carcinoma in a case-control study. Cancer Epidemiol 46:66-72
Cartmel, B; Bale, A E; Mayne, S T et al. (2017) Predictors of tanning dependence in white non-Hispanic females and males. J Eur Acad Dermatol Venereol 31:1223-1228
Stiegler, Amy L; Boggon, Titus J (2017) p190RhoGAP proteins contain pseudoGTPase domains. Nat Commun 8:506
Wu, Mengyun; Zang, Yangguang; Zhang, Sanguo et al. (2017) Accommodating missingness in environmental measurements in gene-environment interaction analysis. Genet Epidemiol 41:523-554
Kahn, Jessica A; Lee, Jeannette; Belzer, Marvin et al. (2017) HIV-Infected Young Men Demonstrate Appropriate Risk Perceptions and Beliefs about Safer Sexual Behaviors after Human Papillomavirus Vaccination. AIDS Behav :
Miller, Chad J; Muftuoglu, Yagmur; Turk, Benjamin E (2017) A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. Biochem Pharmacol 142:39-45

Showing the most recent 10 out of 147 publications