Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

Jing Pan; Yao Chen; Qi Zhang; Achia Khatun; Katie Palen; Gang Xin; Li Wang; Chuanjia Yang; Bryon D. Johnson; Charles R. Myers; Shizuko Sei; Robert H. Shoemaker; Ronald A. Lubet; Yian Wang; Weiguo Cui; Ming You

doi:10.1038/s42003-021-02381-x

Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

Jing Pan, Yao Chen, Qi Zhang, Achia Khatun, Katie Palen, Gang Xin, Li Wang, Chuanjia Yang, Bryon D. Johnson, Charles R. Myers, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Weiguo Cui, Ming You^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8⁺ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4⁺ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.

Original language	English (US)
Article number	906
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02381-x
State	Published - Dec 2021

Funding

We are grateful to Dr. Jonathan M. Kurie (MD Anderson) for providing the LKR13 cells, and to Curis, Inc. for providing CA170. This work was funded by the National Cancer Institute (HHSN26100002, 75N91019D00020-E01, and 75N91019D00020-E04). Drs. Shizuko Sei, Robert H. Shoemaker, and Ronald A. Lubet from NCI participated in the study design and the manuscript editing. This work was also supported by the grants from National Institutes of Health [R01CA223804 (M.Y.; L.W.); R01CA232433 (M.Y.); R01CA223804 (M.Y.); AI125741 (W.C.); R01CA164225 (L.W.); R01AI148403 (W.C.)], America Cancer Society Research Scholar Grant RSG-18-045-01 - LIB (L.W.), and America Cancer Society Research Scholar Grant (W.C.).

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry, Genetics and Molecular Biology
Medicine (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Pan, J., Chen, Y., Zhang, Q., Khatun, A., Palen, K., Xin, G., Wang, L., Yang, C., Johnson, B. D., Myers, C. R., Sei, S., Shoemaker, R. H., Lubet, R. A., Wang, Y., Cui, W., & You, M. (2021). Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA. Communications Biology, 4(1), Article 906. https://doi.org/10.1038/s42003-021-02381-x

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abstract = "Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8+ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine.",

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Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

Abstract

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ASJC Scopus subject areas

UN SDGs

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