DDW ePoster Library

SILENCING OF TUMORAL CARBOHYDRATE SULFOTRANSFERASE 15 AUGMENTS TUMOR-INFILTRATING T CELLS WITH BOOSTED LYMPH NODE T CELL PRIMING IN A MURINE MODEL OF PANCREATIC CANCER
DDW ePoster Library. Ye J. 05/22/22; 354739; Su1264
Dr. Juanjuan Ye
Dr. Juanjuan Ye
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Number: Su1264
SILENCING OF TUMORAL CARBOHYDRATE SULFOTRANSFERASE 15 AUGMENTS TUMOR-INFILTRATING T CELLS WITH BOOSTED LYMPH NODE T CELL PRIMING IN A MURINE MODEL OF PANCREATIC CANCER

Society: AGA
Track: Pancreatic Diseases

Author(s): Juanjuan Ye3, Futoshi Suizu4, Keiko Yamakawa6, Motohiko Kato1, Hiroyuki Yoneyama7, Naohisa Yahagi2, Yoko Matsuda5

Institution(s): 1. Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Byorigaku Kyoshitsu, Shinjuku-ku, Tokyo, Japan. 2. Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Byorigaku Kyoshitsu, Shinjuku-ku, Tokyo, Japan. 3. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 4. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 5. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 6. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 7. TME Therapeutics Inc. Minato-ku, Shinjuku-ku, Tokyo, Japan.

Introduction:
A highly immunosuppressive microenvironment and poor immune infiltration in pancreatic cancer is an obstacle for immune checkpoint inhibition therapies. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. To investigate the role of CHST15 on tumor immune microenvironment, we evaluated the changes in tumor immune cell profiling in a syngeneic mouse model by implanting pancreatic cancer cells with silencing of CHST15 gene.

Methods:
We constructed CHST15 shRNA-transfected mouse pancreatic cancer cell line KPC, confirmed repression of CHST15 protein then used as tumor-specific CHST15 knocked-down KPC (CHST15 KD). Wild-type KPC (WT) or CHST15 KD cells were implanted subcutaneously to left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. Kinetics of immune cell components were analyzed by immunohistochemical staining for both tumor microenvironment and tumor draining lymph node (TDLN) at weeks 1, 2, 3 and 4 after inoculation (n=5-6 at each time point).

Results and Discussion:
In the WT group, tumor growth was accelerated from week 2 to week 4, while the growth was almost completely inhibited in the CHST15 KD group. Quantitative analyses for immunostained tissues at week 4 showed the significant repression of CHST15 in the CHST15 KD group. This was associated with the significant increase of CD3+, CD4+ and CD8+ T cells in tumor microenvironment, while T cells were barely detected in the WT group. A significant number of EdU+ proliferating T cells and Granzyme+ CD8+ T cells were found in the CHST15 KD group compared to the WT group. In the TDLN, EdU+ CD4+ and CD8+ T cells were diminished at week 2 in the WT group, which was prior to rapid tumor expansion. In strikingly contrast, massive proliferation of T cells was observed in the CHST15 KD group from week 2. These results suggest that tumoral CHST15 remotely provides T cell suppressive signal to TDLN and illustrate a novel immunotherapeutic potential of tumoral CHST15 blockade by reactivating T cell immunity in pancreatic cancer.

Conclusion:
The present study demonstrated that blockade of tumoral CHST15 augments the number of activated tumor-infiltrating T cells and inhibits tumor growth in mouse pancreatic cancer. The effect of tumoral T cell accumulation is followed by boosted T cell priming in immune suppressive TDLN. These findings suggest the possibility of a new immunotherapy by enhancing T cell infiltration in refractory pancreatic cancer.
Number: Su1264
SILENCING OF TUMORAL CARBOHYDRATE SULFOTRANSFERASE 15 AUGMENTS TUMOR-INFILTRATING T CELLS WITH BOOSTED LYMPH NODE T CELL PRIMING IN A MURINE MODEL OF PANCREATIC CANCER

Society: AGA
Track: Pancreatic Diseases

Author(s): Juanjuan Ye3, Futoshi Suizu4, Keiko Yamakawa6, Motohiko Kato1, Hiroyuki Yoneyama7, Naohisa Yahagi2, Yoko Matsuda5

Institution(s): 1. Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Byorigaku Kyoshitsu, Shinjuku-ku, Tokyo, Japan. 2. Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Byorigaku Kyoshitsu, Shinjuku-ku, Tokyo, Japan. 3. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 4. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 5. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 6. Kagawa Daigaku Igakubu Daigakuin Igakukei Kenkyuka, Kita-gun, Kagawa, Japan. 7. TME Therapeutics Inc. Minato-ku, Shinjuku-ku, Tokyo, Japan.

Introduction:
A highly immunosuppressive microenvironment and poor immune infiltration in pancreatic cancer is an obstacle for immune checkpoint inhibition therapies. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. To investigate the role of CHST15 on tumor immune microenvironment, we evaluated the changes in tumor immune cell profiling in a syngeneic mouse model by implanting pancreatic cancer cells with silencing of CHST15 gene.

Methods:
We constructed CHST15 shRNA-transfected mouse pancreatic cancer cell line KPC, confirmed repression of CHST15 protein then used as tumor-specific CHST15 knocked-down KPC (CHST15 KD). Wild-type KPC (WT) or CHST15 KD cells were implanted subcutaneously to left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. Kinetics of immune cell components were analyzed by immunohistochemical staining for both tumor microenvironment and tumor draining lymph node (TDLN) at weeks 1, 2, 3 and 4 after inoculation (n=5-6 at each time point).

Results and Discussion:
In the WT group, tumor growth was accelerated from week 2 to week 4, while the growth was almost completely inhibited in the CHST15 KD group. Quantitative analyses for immunostained tissues at week 4 showed the significant repression of CHST15 in the CHST15 KD group. This was associated with the significant increase of CD3+, CD4+ and CD8+ T cells in tumor microenvironment, while T cells were barely detected in the WT group. A significant number of EdU+ proliferating T cells and Granzyme+ CD8+ T cells were found in the CHST15 KD group compared to the WT group. In the TDLN, EdU+ CD4+ and CD8+ T cells were diminished at week 2 in the WT group, which was prior to rapid tumor expansion. In strikingly contrast, massive proliferation of T cells was observed in the CHST15 KD group from week 2. These results suggest that tumoral CHST15 remotely provides T cell suppressive signal to TDLN and illustrate a novel immunotherapeutic potential of tumoral CHST15 blockade by reactivating T cell immunity in pancreatic cancer.

Conclusion:
The present study demonstrated that blockade of tumoral CHST15 augments the number of activated tumor-infiltrating T cells and inhibits tumor growth in mouse pancreatic cancer. The effect of tumoral T cell accumulation is followed by boosted T cell priming in immune suppressive TDLN. These findings suggest the possibility of a new immunotherapy by enhancing T cell infiltration in refractory pancreatic cancer.

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