# Understanding PD-L1/L2 protein regulation, detection and signaling to predict melanoma therapeutic sensitivity

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $182,325

## Abstract

PROJECT SUMMARY/ABSTRACT
Modulators and effectors of anti-PD-1 responsiveness in cancer include T cell infiltration, an immune-
suppressive microenvironment, tumor mutational burden, and tumor cell-intrinsic pathway (e.g., -
catenin) alterations. Cell-surface PD-L1 level has been implicated as a baseline predictive marker of
anti-PD-1 responsiveness, and cell-surface PD-L2 level may have predictive value independent of PD-
L1. In melanoma, MAPK inhibitor therapy strongly induces PD-L1/L2 expression levels in tumor,
stromal and immune cells, suggesting contributions to adaptive resistance. Induction of cell-surface
PD-L1 is central to adaptive immune resistance and implicated as a mechanism of acquired anti-PD-1
resistance. Moreover, the regulation of surface PD-L1 protein stability has been implicated in tumor
immune surveillance, where increased degradation augments tumor-specific T cell activity.
We hypothesize that a better understanding of regulatory mechanisms controlling cell-surface PD-
L1/L2 stability, clinical detection, and tumor cell-intrinsic pro-survival signaling could shed insights into
melanoma immune evasion and therapeutic responsiveness. We will use proteomic approaches to
dissect these processes and to explore the melanoma surface glycoproteome, the PD-L1/L2
interactome and the cytoplasmic signalosome in order to nominate mechanisms and/or markers of
therapeutic responsiveness. We will interrogate iteratively clinical tumor samples and syngeneic mouse
models of Braf, Nras and Nf1 mutant melanoma. These immune-competent models of melanoma are
clinically relevant given their UV-induced high mutational burdens, dependence on CD8 T cells for
therapeutic responses and capability for widespread metastases, including metastases to the brain.
We will use cell-surface labeling of sialic acid-containing glycans to analyze the live cell surface
glycoproteome, co-immunoprecipitation of PD-L1/L2 to enrich for interactomes, and APEX-based
proteomic strategy to define in situ dynamic intracellular PD-L1/L2 neighborhood interactomes in
response to PD-1 ligation or IFN treatment. We will address what regulate PD-L1/L2 ubiquitination,
recycling and degradation, how glycosylation affects membrane PD-L1 immunohistochemical
detection, whether deglycosylation improves prediction of anti-PD-1 responses at baseline and on-
treatment, and how novel cytoplasmic motifs of PD-L1/L2 mediate PD-1-dependent tumor cell pro-
survival signaling. Using proximity ligation assays on clinical melanoma, we will test whether PD-L1/L2
tumor cell-intrinsic signaling reduces therapy efficacy. These proteomic approaches should advance
our understanding of therapy response patterns in metastatic melanoma and nominate predictive
biomarkers and combinatorial targets.

## Key facts

- **NIH application ID:** 10105173
- **Project number:** 1R21CA255837-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ROGER S LO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,325
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105173

## Citation

> US National Institutes of Health, RePORTER application 10105173, Understanding PD-L1/L2 protein regulation, detection and signaling to predict melanoma therapeutic sensitivity (1R21CA255837-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105173. Licensed CC0.

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