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Tumor cell-intrinsic STING signaling role in spontaneous and therapeutic induction of tertiary lymphoid structures

Award Number: K22CA296487
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Tumor cell-intrinsic STING signaling role in spontaneous and therapeutic induction of tertiary lymphoid structures - Title: Tumor cell-intrinsic STING signaling role in spontaneous and therapeutic induction of tertiary lymphoid structures The presence of tertiary lymphoid structures (TLSs) within many human cancer types has been increasingly associated with improved responses to immune checkpoint inhibitors (ICIs), underscoring their prognostic and predictive value. However, the mechanisms triggering their formation and maintenance in cancer remain unknown. Given the selective occurrence of TLSs in certain tumors, it is likely that tumor cell-intrinsic mechanisms are vital in orchestrating TLS assembly. Our earlier findings indicate a critical role of the STING signaling pathway in promoting tumor antigenicity. We have also shown that intact activation of STING in tumor cells induces specific chemokines, which are essential for effector T-cell trafficking within tumors. These chemokines are also among our 12-chemokine gene expression signature, which is predictive of TLS's presence in various human solid tumors, including melanoma. Based on these findings, we postulate that tumor cell- intrinsic STING signaling is a significant determinant in TLS formation. To test this hypothesis, we propose to: (1) Assess if baseline STING status in tumor cells influences the spontaneous formation of TLSs without therapeutic intervention. Using immunotherapy-naïve human melanoma samples, we will test the hypothesis that STING signaling in tumor cells can not only induce chemokines associated with TLS formation but can also reinforce initiation of an intra-tumoral lymphoid niche by regulating their antigenicity and T-cell recognition. (2) Dissect the mechanisms underlying the therapeutic induction of TLSs following pharmacologic activation of STING in melanoma cells. Using Yumm1.7 murine melanoma models, we will test the hypothesis that therapeutic activation of STING signaling in melanoma cells results in the direct induction of T-cell homing chemokines and also triggers a type I IFN signaling cascade, which will lead to the local production of CXCL13 in stromal cells and subsequently increase in B cell recruitment and ectopic germinal center formation. (3) Evaluate the impact of STING agonism on the therapeutic efficacy of ICIs in primary and acquired resistant melanoma models through the induction of TLSs. Using ICI-resistant TLS-absent murine melanoma models, we will test the hypothesis that activation of STING signaling in tumor cells leads to the formation of tumor-localized TLSs, promoting the in situ activation of naïve T lymphocytes in TLSs and improving responses to ICIs. We have developed a strategic plan involving intensive training at the bench and exposure to various educational opportunities at the Moffitt Cancer Center. The proposed experiments and a comprehensive mentorship and didactic plan will position the candidate with a unique set of cross-disciplinary skills that will allow her to transition into a fully 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 = $174,949 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	1	6/8/2026	NEW	$174,949
														Subtotal = $174,949

Grand Total All Awards = $174,949

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Tumor cell-intrinsic STING signaling role in spontaneous and therapeutic induction of tertiary lymphoid structures

Award Number: K22CA296487

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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