Over the past 10 years, studies of the immune microenvironment of cancer in both murine models and in humans has identified intracellular signaling pathways and expression of membrane ligands and receptors that locally inhibit antitumor immune responses. Among the most important are the ligands PD-L1 and PD-L2 that interact with the co-inhibitory receptor PD-1 on activated T cells. PD-1 pathway-blocking antibodies have so far had significant impact in melanoma, renal, lung, bladder, head and neck, and ovarian cancers, and Hodgkin's lymphoma. During the initial R01 funding period, we have made major discoveries regarding regulation of the expression of PD-1 and its ligands, that have important implications for identifying biomarkers and developing combinatorial approaches to cancer immunotherapy. Specifically, we showed that PD-L1 expression in tumors predicts response to PD-1 blockade. This finding has led to the development of PD-L1 IHC tests by several major pharmaceutical companies developing PD-1 pathway blocking drugs. We also demonstrated coordinate expression of PD-L1 and other checkpoint molecules, supporting the clinical development of the anti-PD-1/LAG-3 combination. Finally, we developed major biological and molecular concepts for understanding regulation of PD-1 and its ligands in the tumor microenvironment (TME), namely that expression represents a dynamic cross- talk between tumor cells and TILs. We showed that a dominant mechanism for PD-L1 up-regulation on certain tumors is not constitutive induction but rather adaptive resistance, whereby tumors respond to sensing of immune threat through IFN-g. The adaptive resistance concept now guides thinking in the field. Conversely, we also showed that a major cytokine produced by tumor cells, TGF-b, can enhance TCR-driven PD-1 promoter activity and thus PD-1 expression on T cells. These discoveries from our previous grant period raise a number of additional questions that bear on advances in immunotherapy: Why do some tumor types express PD-L1 adaptively and others constitutively? What are the relative functional roles of PD-L1 expression by tumor cells vs. infiltrating immune cells? Is the expression of PD-1 on TILs regulated in vivo by levels of TGF-b and TGF-b dependent signaling molecules? How heterogeneous is expression of PD-1, PD-L1 and other coordinately regulated checkpoint molecules among metastases in a given patient? Why do many patients with PD-L1+ tumors NOT respond to PD-1 pathway blockers? To answer these questions, we propose three Aims in this competing renewal: 1) Define mechanisms regulating PD-L1 expression by tumor cells and other cell types in the TME; 2) Characterize factors influencing PD-1 expression by T cells; and 3) Characterize immunological mechanisms underlying the clinical effects of PD-L1/PD-1 blockade in cancer therapy, including the co-expression of multiple checkpoint pathways that might provide resistance pathways to therapy.

Public Health Relevance

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 requires a more detailed knowledge of the molecules and pathways involved. Our objectives are 1) to elucidate how interactions of the immune regulatory molecules PD-L1, expressed by cancer cells, and PD-1, expressed by activated antitumor immune cells, support cancer progression; and 2) to use this knowledge to develop more effective cancer immunotherapies based on PD-1 pathway blockade.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Song, Min-Kyung H
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Cottrell, T R; Thompson, E D; Forde, P M et al. (2018) Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol 29:1853-1860
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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