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Characterisation and harnessing the CD8+ Tissue Resident Memory T cell response in HPV-driven anal neoplasia.

Award Number: R21AI162141
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Anal cancer has a rising incidence in the Americas, Australia and parts of Europe, the major risk factor being high-risk human papilloma virus (HR-HPV). However, when a precancerous high- grade squamous intraepithelial lesion (HSIL) develops in HIV-infected hosts only a minority progresses to anal cancer in the absence of treatment, highlighting the existence of effective host immune surveillance. Our project endeavours to define the mucosal T cell mechanisms controlling HSIL progression and harness for novel therapeutic development. We leverage from the successful natural history Study of the Prevention of Anal Cancer (SPANC), that recruited HIV-infected uninfected adult men who attended 6 clinic visits over 3 years. Archived tissue sections of patients with SIL together with an existing rich clinical database represents a significant translational research opportunity. Tissue resident memory T (TRM) cells are specialised lymphocytes adapted for life in tissue, with minimal re-circulation. CD8+ TRM cells are characterised by co-expression of CD103 and CD69 and high expression of inflammatory and cytotoxic markers. There is exciting emerging data for their role in anti-tumour immunity, including in HPV-associated head and neck squamous cell carcinoma (SCC), where the proportion of tumour-infiltrating CD8+ TRM cells positively correlates with prognosis and survival. AIM 1: To quantify total and activated tissue CD8+ TRM cells in HPV16+ and HPV16- SIL and determine if HIV-co-infection has an impact on the size, distribution and phenotype of these populations. AIM 2: To define the molecular characteristics of both the T cell rich zones and stroma of patients with regressive versus persistent high grade HSIL. To determine if the presence of HIV co-infection modulates the expression of these biological pathways. AIM3: To identify novel therapeutic targets that activate CD8+ TRM cells e.g. established or emerging checkpoints PD-1, CTLA-4, LAG-3, CD39 and/or cereblon. This will be the first comprehensive study of TRM cells in anal cancer pathogenesis and the first to examine the effect of co-morbid HIV infection. We will define the role TRM cells play in HSIL regression using cutting-edge multi-plex spectral microscopy, Digital Spatial (RNA) Profiling and single-cell protein-RNASeq, providing a sound foundation for advancements of novel therapeutics development aimed at decreasing the significant burden of this disease.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF NEW SOUTH WALES	HIGH ST	KENSINGTON				AUS	Allergy and Infectious Diseases Research	000	2	7/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF NEW SOUTH WALES	HIGH ST	KENSINGTON				AUS	Allergy and Infectious Diseases Research	000	2	6/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $121,306 )
2022	2022	UNIVERSITY OF NEW SOUTH WALES	HIGH ST	KENSINGTON				AUS	Allergy and Infectious Diseases Research	000	2	7/14/2022	NON-COMPETING CONTINUATION	$121,306
														Subtotal = $121,306

Issue Date FY: 2021 ( Subtotal = $148,306 )
2021	2021	UNIVERSITY OF NEW SOUTH WALES	HIGH ST	KENSINGTON	NSW			AUS	Allergy and Infectious Diseases Research	000	1	6/21/2021	NEW	$148,306
														Subtotal = $148,306

Grand Total All Awards = $269,612

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Characterisation and harnessing the CD8+ Tissue Resident Memory T cell response in HPV-driven anal neoplasia.

Award Number: R21AI162141

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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