# PD-1/PD-L1 modulation in cancer therapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $588,135

## Abstract

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...

## Key facts

- **NIH application ID:** 10355495
- **Project number:** 5R01CA142779-12
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** DREW M. PARDOLL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $588,135
- **Award type:** 5
- **Project period:** 2010-06-21 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355495

## Citation

> US National Institutes of Health, RePORTER application 10355495, PD-1/PD-L1 modulation in cancer therapy (5R01CA142779-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355495. Licensed CC0.

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