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The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.

Award Number: R01AI164744
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer. - Project Summary Chronic infection and cancer are associated with suppressed T cell responses resulting in the inability to control these diseases. Over the last 15 years, blockade of negative immune regulators has proven effective in a small number of cancer patients and shown promise in animal models of chronic viral infection. Despite these encouraging results, no effective immune therapies exist for chronic viral infection and most patients fail to respond or develop resistance to checkpoint blockade. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells which sustain T cell responses during persistent infection and cancer. Importantly, these cells generate the major proliferative burst observed following anti-PD1 treatment. Further, the numbers of TCF1+ CD8 T cells in tumors correlate with favorable responses to anti-PD-1 treatment. As such, approaches to expand these cells are actively sought. We recently reported that blockade of interferon type 1 (IFN-I) receptor leads to expansion of CXCR5+ CD8+ T cells in an IL-27-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific exhausted CD8+ T cells. We found that CD8+ T cell-intrinsic IL-27 signaling promotes the TCF1-high cells to maintain proliferation and avoid programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings revealed that IL-27 is essential for the expansion of TCF1+ CD8 T cells following persistent viral infection. We hypothesize that IL-27 produced by specific cell subsets is necessary to safeguard rapidly diving CD8 T cells from apoptotic cell death during both persistent viral infection and cancer. We propose in this application to explore the basic biology of IL-27 signaling as it relates to CD8 T cell expansion, survival and function. We will assess the cellular populations and signals that induce IL-27 production, assess how IL-27 prevents apoptosis of rapidly diving TCF1+ CD8 T cells and expand our exploration into whether IL-27 signaling following anti-PD-1/L1 treatment during persistent LCMV infection and syngeneic tumors is crucial for the CD8 T cell expansion/function. Once completed these studies will provide important basic knowledge of how IL-27 regulates anti-viral and anti-tumor responses. Moreover, findings from this study should point the way to treatments and modalities that can be employed to sustain optimal T cells responses.


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: 2025 ( Subtotal = $557,334 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	7/2/2025	NON-COMPETING CONTINUATION	$557,334
														Subtotal = $557,334

Issue Date FY: 2024 ( Subtotal = $548,247 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	6/14/2024	NON-COMPETING CONTINUATION	$548,247
														Subtotal = $548,247

Issue Date FY: 2023 ( Subtotal = $548,247 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	6/22/2023	NON-COMPETING CONTINUATION	$548,247
														Subtotal = $548,247

Issue Date FY: 2022 ( Subtotal = $537,646 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	6/21/2022	NON-COMPETING CONTINUATION	$537,646
														Subtotal = $537,646

Issue Date FY: 2021 ( Subtotal = $537,646 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/6/2021	NEW	$537,646
														Subtotal = $537,646

Grand Total All Awards = $2,729,120

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The role of IL-27 in sustaining the exhausted CD8 T cell response to persistent infection and cancer.

Award Number: R01AI164744

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/06/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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