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Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy

Award Number: R01CA267554
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy - Project Summary/Abstract Chemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painful neuropathy, posing a major challenge to the successful treatment of cancer. Recent reports demonstrate that male mice lacking T cells have prolonged mechanical hypersensitivity after treatment with paclitaxel (PTX), and only the intravenous transfer of CD8+, but not CD4+, T cells reduced the hypersensitivity. Our preliminary in vivo data demonstrates female mice have 2-fold more CD4+ T cells in the DRG than male and ovariectomized (OVX) female mice, and neuronal injury induced by PTX robustly increases anti-inflammatory CD4+ T cells in the DRG only in estrogen-competent female mice. CD4+ T cell depletion in female mice prior to PTX results in an increase in mechanical hypersensitivity 3 days post-PTX. Our results suggest a previously unexplored hormone and sex difference in CD4+ T cells and the severity of chemotherapy-induced peripheral neuropathy (CIPN). PTX is primarily used to treat ovarian, breast, and non-small cell lung cancer with post- menopausal patients at an increased risk of CIPN; therefore, preventative measures would be invaluable for women. The mechanism by which CD4+ T cells reduce the severity of PIPN is unknown. In our preliminary studies, DRG neurons from female mice have the capacity to activate CD4+ T cells to secrete anti- inflammatory cytokines. Published RNA-seq datasets of DRG neurons show that DRG neurons express MHCII, a protein directly involved in T cell activation. Our central hypothesis is that PTX administration in female mice increases MHCII on sensory neurons to stimulate the paracrine release of anti-inflammatory cytokines by resident CD4+ T cells to suppress CIPN. In Aim 1, we will determine the extent to which estrogen- driven CD4+ T cells reduce the severity of PTX-induced peripheral neuropathy. Estrogen is known to induce proliferation of blood CD4+ T cells, but it is unknown if this occurs in the DRG. We predict that estrogen signaling in CD4+ T cells will increase the number of resident CD4+ T cells in the DRG to secrete anti- inflammatory cytokines in response to PTX. We expect CD4+ T cells to ameliorate CIPN in female, but not male mice. In Aim 2, we will quantify the extent PTX can enhance MHCII on DRG neurons to induce anti- inflammatory CD4+ T cell cytokine production. We predict PTX-induced inflammation will increase neuronal MHCII to elicit an anti-inflammatory CD4+ T cell response in the DRG of female, but not male mice. In Aim 3, we will determine the degree in vivo activation of neuroprotective CD4+ T cells can reduce and reverse PTX- induced peripheral neuropathy. We predict that activated CD4+ T cells will dampen and reverse CIPN in female, but not male mice, unless pre-treated with estrogen. Completion of these aims will provide compelling evidence that CD4+ T cells in the DRG of females are neuroprotective and anti-nociceptive, and can be exploited to prevent or resolve CIPN. Neuronal MHCII-dependent activation of CD4+ T cells represents a novel mechanism for neuro-immune communication that could be utilized for therapeutic intervention.


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 = $342,189 )
2025	2025	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Cancer Treatment Research	000	4	6/30/2025	NON-COMPETING CONTINUATION	$342,189
														Subtotal = $342,189

Issue Date FY: 2024 ( Subtotal = $325,079 )
2024	2024	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Cancer Treatment Research	000	3	7/3/2024	NON-COMPETING CONTINUATION	$325,079
														Subtotal = $325,079

Issue Date FY: 2023 ( Subtotal = $341,745 )
2023	2023	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Cancer Treatment Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$341,745
														Subtotal = $341,745

Issue Date FY: 2022 ( Subtotal = $342,189 )
2022	2022	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Cancer Treatment Research	000	1	8/12/2022	NEW	$342,189
														Subtotal = $342,189

Grand Total All Awards = $1,351,202

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Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy

Award Number: R01CA267554

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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