Intraepithelial ILC1-like Natural Killer Cells Increase Lymphocyte Infiltration into the Tumor Microenvironment via CXCL10

Sunday, September 29, 2024

10:06 AM – 10:12 AM EDT

Location: MBCC, 208

Disclosure(s):

Sainiteesh Maddineni, BS:

faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

Krishna Sharma:

faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

Imran A. Mohammad, PhD:

faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

June Ho Shin, PhD:

faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

Introduction: Natural killer (NK) cells are important innate immune cells involved in the anti-tumor response. Intraepithelial ILC1-like (ieILC1-like) NK cells are a tissue-resident, cytotoxic subset of NK cells found in the microenvironment of head and neck squamous cell carcinoma (HNSCC). The interactions of these ieILC1-like NK cells with the surrounding tumor microenvironment are unexplored. Here, we evaluate how ieILC1-like NK cells may influence other immune cell behaviors, including T cell trafficking to tumors.

Methods: We generated cytotoxic CD56+CD49a+CD103+ ieILC1-like NK cells by co-culturing peripheral blood NK cells with IL-15 and HNSCC cells in vitro. We implanted K562 tumors in the flanks of NSG immunodeficient mice and administered ieILC1-like NK cells or conventional NK cells intratumorally with human T cells given intravenously. After 24 hours, we extracted tumors and analyzed the microenvironment for T cell infiltration via flow cytometry. We also co-cultured ieILC1-like NK cells with tumor cells and analyzed cytokines in the supernatant via Luminex immunoassay.

Results: The ieILC1-like NK cell-injected tumors accumulated more CD3+ T cells in the tumor microenvironment compared to tumors with conventional NK cells (cNKs) or no NK cells. Moreover, tumors injected with ieILC1-like NK cells had a larger ratio of T cells to NK cells compared to tumors with cNK cells. Luminex assays revealed CXCL10 as a cytokine that was significantly elevated in the cultured supernatants of ieILC1-like NK cells stimulated with tumor cells but not the supernatants of stimulated cNKs or unstimulated ieILC1-like NK cells. On flow cytometry analysis, we found that ieILC1-like NK cells produce robust amounts of IFNy, a known CXCL10 inducer, while the CXCL10 was produced by the tumor cells.

Conclusions: These results indicate that ieILC1-like NK cells induce tumor production of CXCL10, a pro-inflammatory chemokine that can promote T cell infiltration into the tumor microenvironment. The role of ieILC1-like NK cells in modulating clinical responses to immune checkpoint blockade warrants investigation.

Presenting Author(s)

Sainiteesh Maddineni, BS

Medical Student
Stanford University School of Medicine
San Ramon, CA, United States

Disclosure(s):
faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

Co-Author(s)

KS

Krishna Sharma

Undergraduate Student
Stanford University School of Medicine
San Ramon, CA, United States

Disclosure(s):
faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.
IM

Imran A. Mohammad, PhD

postdoc
Stanford University School of Medicine
STANFORD, CA, United States

Disclosure(s):
faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.
JS

June Ho Shin, PhD

sr scientist
Stanford University School of Medicine
palo alto, CA, United States

Disclosure(s):
faculty for this accredited education activity has no relationship(s) with ineligible companies to disclose.

Senior Author(s)

JS

John Sunwoo, MD

Associate Professor of Otolaryngology-Head and Neck Surgery
Stanford School of Medicine, Department of Otolaryngology-Head and Neck Surgery
Stanford, California, United States

Disclosure information not submitted.