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Role of sensory nerves in the regulation of anti-tumor immunity

Award Number: R01CA302957
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Role of sensory nerves in the regulation of anti-tumor immunity - Project Summary In the last decade it has become clear that the peripheral nervous system, including sensory (afferent) and autonomic neurons, is a critical component of the tumor microenvironment (TME). Multiple studies showed that denervation slows or prevents the initiation, growth and metastasis of many cancer types including breast, pancreatic, prostate, gastric and oral squamous cell carcinomas, and melanoma. Therefore, tumor innervation is widely considered pro-tumorigenic, supported by findings that denser intratumoral innervation leads to poorer survival in multiple cancers. We and others discovered that sensory denervation of melanoma significantly slows tumor growth via effector CD8 exhaustion, inhibition of tertiary lymphoid structures, cancerassociated nerve injury and other potential mechanisms. Our new data show that afferents which innervate melanoma tumors and their associated tumor-draining lymph nodes (TDLN) are located in same dorsal root ganglia, but are distinct cells, and coordinately modulate immune responses within the TME and the secondary lymphoid organs. Mechanisms of neuro-immune modulation in melanoma TME and TDLN are still poorly understood, yet preservation of TDLN prior to neo-adjuvant immunotherapy is quickly becoming a standard of care for melanoma and other solid tumors, suggesting that TDLN innervation may be a novel therapeutic target. Our hypothesis explaining the efficacy of denervation in the setting of melanoma is that during tumor progression, neurons inhibit secondary and tertiary lymphoid organ functions, thus preventing de novo anti-melanoma-specific immune responses. To test this hypothesis, reveal the underlying mechanisms and examine the therapeutic potential of targeting TDLN innervation, we propose three specific aims. Using retrograde-labeling, optogenetics and tissue-specific ablation of neurons, in Aim 1 we will identify which sensory neurons are responsible for suppressing protective immune responses in melanoma TME and TDLN. In Aim 2, we will elucidate neuro-immune and neuro-endothelial signaling mechanisms governing the inhibition of anti-melanoma immune responses by TDLN innervation, focusing on substance P/NK1R and CGRP/Ramp1 axes. In Aim 3, we will test in novel mouse models whether denervating TDLN in combination with immune checkpoint inhibitors as a neoadjuvant approach improves the response to immunotherapy and increases survival. Without the utilization of specific proposed mouse animal models, preclinical mechanistic and feasibility studies which will enable clinical translation will not be possible. This project may not only lead to more effective treatment options for patients with advanced melanoma but for patients with other malignancies such as lung or breast cancer where existing immunotherapy-based protocols frequently fail to achieve complete and durable 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: 2027 ( Subtotal = $0 )
2027	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	10/20/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $665,449 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	7/7/2026	NEW	$665,449
														Subtotal = $665,449

Grand Total All Awards = $665,449

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Role of sensory nerves in the regulation of anti-tumor immunity

Award Number: R01CA302957

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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