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

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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.

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

ASJC Scopus subject areas

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

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10.1038/s42003-021-02381-x

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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), [906]. https://doi.org/10.1038/s42003-021-02381-x

Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA. / Pan, Jing; Chen, Yao; Zhang, Qi; Khatun, Achia; Palen, Katie; Xin, Gang; Wang, Li; Yang, Chuanjia; Johnson, Bryon D.; Myers, Charles R.; Sei, Shizuko; Shoemaker, Robert H.; Lubet, Ronald A.; Wang, Yian; Cui, Weiguo; You, Ming.

In: Communications Biology, Vol. 4, No. 1, 906, 12.2021.

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

Pan, Jing ; Chen, Yao ; Zhang, Qi ; Khatun, Achia ; Palen, Katie ; Xin, Gang ; Wang, Li ; Yang, Chuanjia ; Johnson, Bryon D. ; Myers, Charles R. ; Sei, Shizuko ; Shoemaker, Robert H. ; Lubet, Ronald A. ; Wang, Yian ; Cui, Weiguo ; You, Ming. / Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA. In: Communications Biology. 2021 ; Vol. 4, No. 1.

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title = "Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA",

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.",

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

note = "Funding Information: 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.). Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s42003-021-02381-x",

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AU - Pan, Jing

AU - Chen, Yao

AU - Zhang, Qi

AU - Khatun, Achia

AU - Palen, Katie

AU - Xin, Gang

AU - Wang, Li

AU - Yang, Chuanjia

AU - Johnson, Bryon D.

AU - Myers, Charles R.

AU - Sei, Shizuko

AU - Shoemaker, Robert H.

AU - Lubet, Ronald A.

AU - Wang, Yian

AU - Cui, Weiguo

AU - You, Ming

N1 - Funding Information: 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.). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - 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

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