# The CXCR3 Chemokine System in Cancer Immunotherapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $376,216

## Abstract

The recent approval of immune checkpoint blockade, such as anti-PD-1, has marked a milestone in cancer
therapy. Checkpoint blockade “reinvigorates” an “exhausted” anti-tumor T cell response, which can result in a
durable clinical response. However, only a fraction of patients respond to immune checkpoint blockade, and it
only works in a subset of cancers. Improving the efficacy of checkpoint blockade is of paramount importance
and is seemingly within reach but will require a better understanding of the molecules that control the complex
interactions of immune cells in the tumor micro-environment (TME) required for effective checkpoint blockade
therapy. Chemokines are chemotactic cytokines that orchestrate the migratory behavior and cellular
interactions of leukocytes, and therefore have great impact upon anti-tumor immune responses. CXCR3 is a
chemokine receptor for the interferon-inducible chemokines - CXCL9, CXCL10, and CXCL11- and is highly
expressed on CD4+ Th1 cells and CD8+ T effector (Teff) cells. CXCR3 ligands have been correlated with the
presence of Teff within tumors and disease free survival. We have exciting data that CXCR3 is required for
anti-PD-1 immunotherapy. Based on the importance of CXCR3 for T cell recruitment to sites of inflammation, it
is logical to predict that CXCR3 plays an important role in Teff entry into tumors following anti-PD-1 therapy.
However, recent provocative preliminary data leads us to believe that CXCR3 is playing even more important
roles within the tumor following anti-PD-1, and is likely critical to “jump start” the anti-tumor immune response
in the TME. Recent studies have revealed heterogeneity in exhausted T cell (Tex) populations and defined Tex
subsets that differ in their potential for reinvigoration by PD-1 blockade. We have found that CXCR3
expression on Teff inversely correlates with markers of exhaustion. We hypothesize that CXCR3 plays a
functional role in the ability of Tex to become reinvigorated within the tumor following PD-1 blockade. In Aim 1,
we will define the mechanisms by which CXCR3 contributes to the efficacy of PD-1 blockade therapy for
cancer. This will include examining whether CXCR3 plays a critical role enhancing the interaction of Tex with
the most relevant activated antigen-presenting cells in the tumor and facilitating the ability of Teff to locate and
kill cancer cells following anti-PD-1 therapy. In Aim 2, we will determine if augmenting the CXCR3 chemokine
system can improve the efficacy of anti-PD-1 therapy as well as convert anti-PD-1 nonresponsive tumors into
responsive tumors. We will also determine if counter-regulatory mechanisms within the tumor, such as
epigenetic silencing and CXCR3-expressing regulatory T cells, limit the effectiveness of anti-PD-1 therapy by
suppressing CXCL9 and CXCL10 expression in tumors. If these pathways limit CXCR3+CD8+ T cell function in
the tumor, we will devise strategies to circumvent these counter-regulatory responses. Finally, we...

## Key facts

- **NIH application ID:** 9829035
- **Project number:** 5R01CA204028-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ANDREW D LUSTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,216
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829035

## Citation

> US National Institutes of Health, RePORTER application 9829035, The CXCR3 Chemokine System in Cancer Immunotherapy (5R01CA204028-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9829035. Licensed CC0.

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