# Project 2 - Modulation of Anti-Tumor Immunity by Inhibitory Receptors

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $401,814

## Abstract

PROJECT SUMMARY
Cell surface inhibitory receptors (IRs) PD1 and LAG3 control cellular signaling and critical cell intrinsic effector
T cell function and differentiation. Yet, these IRs are also expressed on exhausted intratumoral T cells, limiting
disease clearance. IRs are critical to maintain immune control, but also represent a major barrier to effective
anti-tumor immunity. PD1 and LAG3 are synergistic in multiple diseases, including cancers, and many CD8+ and
CD4+ tumor-infiltrating lymphocytes (TILs) express PD1/LAG3. Indeed, we showed that tumor immunotherapy
targeting PD1/LAG3 can induce almost complete remission of tumors in mice, and clinical evidence now supports
the benefit of single (anti-PD1) or dual (anti-PD1/LAG3) IR blockade. This project will test the central hypothesis
that “PD1 and LAG3 synergize to enforce tumor-induced tolerance using a combination of overlapping and
unique cell intrinsic and extrinsic functions in CD4+ and CD8+ effector T cells”. Due to potency of tolerance in the
tumor microenvironment (TME), mouse models represent an outstanding system to study IR mechanisms to
compare with processes in autoimmune (Project 1) and chronic viral settings (Project 3). We will pursue 3 Aims:
AIM 1: What are the relative and synergistic contributions of PD1 and LAG3 in limiting the initial CD8+ T
cell anti-tumor effector response? We hypothesize that “PD1 and LAG3 do not initiate but temporally re-
enforce progression toward CD8+ T cell exhaustion by limiting population dynamics, differentiation, metabolic
health, and polyfunctionality”. We will use a Quad AT system that co-transfers tumor-specific CD8+ T cells that
are wild-type or lack PD1 and/or LAG3 for functional and transcriptional analysis in the same microenvironment.
AIM 2: What are the relative and synergistic contributions of PD1 and LAG3 in limiting initial CD4+ Tconv
anti-tumor effector response? We hypothesize that “PD1/LAG3 have synergistic effects on CD4+ Tconv cells
by differentially modulating their function and capacity for CD8+ T cell help”. We will interrogate the role of
PD1/LAG3 on CD4+ T cells using our novel CreERT2 line to delete alleles in CD4+ Tconv but not CD8+ T cells or
T regs .
AIM 3: What is the impact of PD1/LAG3 on the durability of anti-tumor T cell memory and maintenance
of systemic immunity? We hypothesize that “PD1 and/or LAG3 limit durability of anti-tumor immunity by
impacting Tex reinvigoration and Tconv cell memory development and maintenance, blunting their recall response
and limiting systemic immunity”. We will ask 2 questions: (A) What is the impact of PD1/LAG3 loss on Tex and
their reinvigoration? (B) What is the impact of PD1/LAG3 on maintenance of T cell anti-tumor memory and recall
response?
PPG Interactions: Project 2 will collaborate with Project 1 to compare the impact of PD1/LAG3 loss on CD4+
T cell function in autoimmune versus tumoral settings; with Project 3 to compare CD8+ T cell exhaustion induced
by tumors or chronic...

## Key facts

- **NIH application ID:** 10023669
- **Project number:** 2P01AI108545-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dario AA Vignali
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,814
- **Award type:** 2
- **Project period:** 2015-05-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023669

## Citation

> US National Institutes of Health, RePORTER application 10023669, Project 2 - Modulation of Anti-Tumor Immunity by Inhibitory Receptors (2P01AI108545-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10023669. Licensed CC0.

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