Over the past decade, studies of the immune microenvironment of cancer in both murine models and 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 immune cells. In the clinic, six unique PD-(L)1 blocking antibodies have had significant impact against a diverse range of advanced solid tumors, and have so far been approved by the FDA for 17 different disease indications. Furthermore, immunohistochemistry testing for PD-L1 expression in pretreatment tumor biopsies, correlated in our early studies with anti-PD-1 clinical response, has been translated into 4 different commercial tests currently approved in specific cancer types to identify patients with an increased likelihood of treatment response. The current challenge, which will be addressed in this proposal, is to understand mechanisms underlying anti-PD-(L)1 resistance in individual patients and across cancer types, affecting ~80% of patients receiving these drugs. Why do many patients with PD-L1+ tumors NOT respond to PD-1 pathway blockers? Why do some responders subsequently relapse? Why are some tumor types particularly resistant to this form of immunotherapy? During the past R01 funding period, major discoveries were made regarding regulation of the expression of PD-1 and its ligands, having important implications for identifying biomarkers and developing combinatorial approaches to cancer immunotherapy. A dominant mechanism for PD-L1 upregulation on certain tumors was revealed as not being constitutive induction but rather adaptive resistance, whereby tumors respond to ?sensing? of immune threat through IFN-g. Conversely, a major cytokine produced by tumor cells, TGF-b, was shown to enhance TCR-driven PD-1 promoter activity and thus PD-1 expression on T cells, and the associated molecules GARP and Activin receptor type 1C were revealed to play pivotal roles in sustaining Treg immunosuppression in the TME. Finally, tumor-intrinsic resistance mechanisms identified by unbiased gene expression profiling emerged as critical determinants of anti-PD-(L)1 failure. In parallel, significant advances in multi-dimensional tissue imaging with the so-called ?AstroPath? platform have revolutionized our ability to interrogate the TME, by capturing and analyzing spatially annotated quantitative data. This competing renewal will characterize the nature of anti-PD-(L)1 tumor resistance by addressing three Aims: 1) Identify Treg molecules selectively expressed in PD-(L)1 non-responders; 2) Define tumor cell-intrinsic pathways mediating anti-PD-(L)1 resistance; and 3) Characterize immune cell and stromal factors underlying anti-PD(L)1 response/resistance. These studies are anticipated to translate into the development of new biomarkers and treatment combinations, enhancing the efficacy of anti-PD-(L)1.

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. Despite recent advances in anti-PD-(L)1 therapies in over a dozen different cancer types, treatment resistance remains a major unsolved clinical problem. Our objectives are 1) to characterize intratumoral factors, including immune cell, tumor cell, and stromal components, underlying anti-PD-(L)1 resistance; and 2) to use this knowledge to develop more effective cancer immunotherapies based on PD-1 pathway blockade, by co-targeting additional tumor immune resistance pathways.

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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