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Modulating regulatory T cell and cancer cell plasticity through TIGIT and PD-1 blockade in human glioblastoma

Award Number: K08CA304352
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Modulating regulatory T cell and cancer cell plasticity through TIGIT and PD-1 blockade in human glioblastoma - ABSTRACT This proposal for a Mentored Clinical Scientist Research Career Development Award (KOS) outlines a comprehensive training program to help Dr. Benjamin Y. Lu prepare for an independent academic research career as a physician-scientist. The scientific goal of this proposal is to define how the immune checkpoints, TIGIT and PD-1, regulate immune cell interactions with cancer cells in human glioblastoma (GBM), which is the most common and universally lethal type of brain tumor with few treatment options. Leveraging exclusive access to clinical samples collected through a phase IB clinical trial investigating pre-surgical anti-TIGIT, anti-PD-1, the combination, or placebo treatment in patients with recurrent GBM, we will dissect the mechanisms by which antiTIGIT and anti-PD-1 modulate anti-tumor immunity in human GBM. In Aim 1, we will explore our hypothesis that TIGIT and PD-1 regulate different aspects of regulatory T cell (Treg) function, and that the addition of anti-TIGIT will uniquely reduce their suppressive function. We will then use high-resolution single-cell sequencing to examine the phenotypic plasticity of Tregs in the context of the global immune microenvironment in resected tumors following neoadjuvant therapy. In Aim 2, we will investigate the mechanisms by which Tregs promote the differentiation of cancer cells into more aggressive, mesenchymal-like states through the TIGIT/CD155 axis using patient-derived GBM neurospheres. We will then use high-resolution single-cell and spatial sequencing to profile resected tumors and assess how each treatment impacts cancer cell states. Findings from this proposal will advance our understanding of the mechanisms underlying combinatorial immune checkpoint therapy. If successful, the results of this proposal also have the potential to broaden the paradigm for how immune checkpoints may influence both immune cell and cancer cell function. The career development plan in this proposal was designed to help Dr. Lu to broaden his expertise in neuroimmunology, acquire expertise in cancer biology, and undergo advanced training in both experimental and bioinformatics methods. Dr. Lu's primary mentor, Dr. David A. Hafler is a renowned physician-scientist with expertise in neuroimmunology and human Treg biology. Dr. Lu will also be guided by his Scientific Advisory Committee, composed of pioneers in glioma biology, single cell and spatial multi-omics, systems immunology, and clinical neuro-oncology (Dr. Roel Verhaak, Dr. Rong Fan, Dr. John Tsang, and Dr. Sylvia Kurz). Dr. Lu will be conducting his research in a highly collaborative, scientifically enriched environment at the Yale School of Medicine, which has strong research programs in immunology and cancer biology and an established track record for supporting physician-scientists. The experience, knowledge, and skills gained through this career development proposal will provide the foundation of Dr. Lu's independent research program and facilitate his success as an independent investigator.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $290,944 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	5/12/2026	NEW	$290,944
														Subtotal = $290,944

Grand Total All Awards = $290,944

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Modulating regulatory T cell and cancer cell plasticity through TIGIT and PD-1 blockade in human glioblastoma

Award Number: K08CA304352

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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