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Modulation of tumor inflammatory factor for immune therapy

Award Number: R01CA208703
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Modulation of tumor inflammatory factor for immune therapy - The study of tumor-associated inflammatory factors is essential for determining the relationship between the tumor microenvironment and tumorigenesis. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) within the tumor microenvironment have been shown to promote tumor progression and metastasis. Despite the initial promise of T cell checkpoint inhibitor therapies in treating cancer patients, the immunosuppressive tumor-promoting microenvironment established by TAMs and MDSCs remains a major barrier to complete success. Using qPCR superarrays, we identified an important tumor factor, CKLF-like MARVEL transmembrane domain containing 4 (CMTM4), a member of the chemokine-like factor superfamily, which is highly expressed in human and mouse tumor cells and tissues. Preliminary studies showed that CMTM4 plays a significant role in the regulation of tumor-associated inflammation and establishment of a suppressive tumor microenvironment. siRNA knockdown (KD) of CMTM4 in tumor led to a significant reduction in tumor growth and angiogenesis in multiple tumor types. Myeloid specific CMTM4 deficiency results in significantly retarded tumor development in transplanted tumor models. Most interestingly, myeloid cells from CMTM4 KO mice skew toward M1 classical functional activation and maturation, which, in turn, plays an important role in the regulation of inflammatory cytokines and inflammation-related transcription factors (e.g. IL-6, TNFalpha, IL- 1beta, NFkappaB, HIF1alpha, IRF5, and IRF8). We hypothesize that CMTM4 is a key factor in controlling inflammatory signals and subsequently affects the tumor microenvironment through recruitment and differentiation of MDSCs toward an “M2-like”, alternatively activated, phenotype that promotes angiogenesis and immune evasion, thereby facilitating tumor progression. Therefore, modulation of CMTM4-regulated inflammatory responses may convert an immune-suppressive tumor microenvironment into an immune- conducive one. In this proposal, three specific aims will be pursued to test our hypothesis: 1) CMTM4 is the key driver that controls tumor inflammation. 2) Modulate the function of myeloid cells through CMTM4. Studies of the cellular and molecular mechanisms of action utilized by CMTM4 are critical for clinical translation. CMTM4 KD can alter the tumor microenvironment, enhance anti-tumor immunity, and control tumor cell progression. Successful completion of these studies will lead to a better understanding of how our findings with mouse CMTM4 can be translated to human studies. The scientific information gained will have a significant impact on targeting TAMs/MDSC to revert the immune suppression associated with advanced malignancies and facilitate development of a novel therapeutic modality for the regulation of chronic inflammatory diseases.


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 = $0 )
2026	2021	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	5	1/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	5	7/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	5	9/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $463,463 )
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	5	9/2/2021	NON-COMPETING CONTINUATION	$463,463
														Subtotal = $463,463

Issue Date FY: 2020 ( Subtotal = $463,463 )
2020	2020	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	4	8/7/2020	NON-COMPETING CONTINUATION	$463,463
														Subtotal = $463,463

Issue Date FY: 2019 ( Subtotal = $449,561 )
2019	2019	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	3	8/7/2019	NON-COMPETING CONTINUATION	$449,561
														Subtotal = $449,561

Issue Date FY: 2018 ( Subtotal = $463,463 )
2018	2018	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	2	8/2/2018	NON-COMPETING CONTINUATION	$463,463
														Subtotal = $463,463

Issue Date FY: 2017 ( Subtotal = $461,550 )
2017	2017	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Detection and Diagnosis Research	000	1	9/21/2017	NEW	$461,550
														Subtotal = $461,550

Grand Total All Awards = $2,301,500

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Modulation of tumor inflammatory factor for immune therapy

Award Number: R01CA208703

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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