Tumor Nuclear YAP1 Expression Status and Molecular Characteristics in relation to Immune Response to Colorectal Carcinoma
Authors: Borowsky Jennifer , Du Chunxia , Kosumi Keisuke , Hamada Tsuyoshi , Morikawa Teppei , da Silva Annacarolina , Nosho Katsuhiko , Nowak Jonathan A. , Nishihara Reiko , Lennerz Jochen K. , Giannakis Marios , Chan Andrew T. , Meyerhardt Jeffrey A. , Fuchs Charles S. , Ogino Shuji 
Published: June 2021

The YAP1 protein is considered as a transcriptional co‐activator, and nuclear YAP1 can combine with TEAD (TEA domain transcription factors) to promote proliferation of colorectal cancer cells. Experimental evidence suggests that the YAP1 protein may increase production of PTGS2 (cyclooxygenase‐2) and inflammatory mediators including prostaglandin E2 (PGE2) and IL6 (Interleukin‐6) in tumor cells such as colon cancer cells. The PTGS2/PGE2 pathway and IL6 play a pivotal role in recruiting myeloid‐derived suppressor cells into the tumor microenvironment, thereby inhibiting anti‐tumor immune response. Therefore, we hypothesized that tumor nuclear YAP1 expression level might be inversely associated with immune response to colorectal cancer.

Using 682 rectal and colon carcinoma cases in the Nurses' Health Study and Health Professionals Follow‐up Study, we examined tumor nuclear YAP1 expression by immunohistochemistry. Multivariable logistic regression models were used to assess the association of nuclear YAP1 expression (negative, low, or high) with histopathologic lymphocytic reaction patterns, and densities of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells, adjusting for potential confounders, including microsatellite instability status, CpG island methylator phenotype status, long‐interspersed nucleotide element‐1 methylation level, and KRAS, BRAF and PIK3CA mutations.

Nuclear YAP1 expression level was inversely associated with CD3+ cell density (for a unit increase in tertile categories of CD3+ cell density as an outcome: multivariable‐adjusted odds ratio, 0.47; 95% confidence interval, 0.33 to 0.67; Ptrend < 0.0001), and CD8+ cell density (for a unit increase in tertile categories of CD8+ cells as an outcome: multivariable‐adjusted odds ratio, 0.49; 95% confidence interval, 0.34 to 0.71; Ptrend = 0.0001). The expression of nuclear YAP1 was not significantly associated with histopathologic lymphocytic reaction patterns, or the density of CD45RO+ cells or FOXP3+ cells (with the adjusted α level of 0.006 for multiple hypothesis testing).

In summary, tumor nuclear YAP1 expression level is inversely associated with the densities of CD3+ cells and CD8+ cells in colorectal carcinoma tissue. Our findings support an important role of YAP1 in regulating anti‐tumor immune response to colorectal cancer.

Support or Funding Information

This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; U01 CA167552 to W.C. Willett and L.A. Mucci; P50 CA127003 to C.S.F.; R01 CA118553 to C.S.F.; R01 CA169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; K07 CA190673 to R.N.; and K07 CA188126 to X.Z.); by Nodal Award from the Dana‐Farber Harvard Cancer Center (to S.O.); and by grants from the Project P Fund, The Friends of the Dana‐Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance, and by Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (to C.S.F. and M.Gi.). J.B. was supported by the Australia Awards‐Endeavour Scholarships and Fellowships Program. K.K. was supported by grants from Overseas Research Fellowship (JP2017‐775) from Japan Society for the Promotion of Science. T.H. was supported by a fellowship grant from the Mitsukoshi Health and Welfare Foundation. T.H. was supported by a fellowship grant from the Mitsukoshi Health and Welfare Foundation. L.L. was supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant from Huazhong University of Science and Technology. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.