Page 122 - D. Cancer biology

[D. Cancer biology-76]

The role of senescent tumor cells in colorectal cancer

progression

Soon Sang Park¹˙², Ga-Yeon Lee¹˙², Young-Kyoung Lee Lee¹, Young-Sam Kim¹˙², Tae-Gyu Kim²˙⁴,

Yong Won Choi¹˙³, Jang-Hee Kim⁴, Tae Jun Park¹˙²˙⁵

¹Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 16499, Korea,
Republic of, ²Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Ajou University

Graduate School of Medicine, Suwon 16499, Korea, Republic of, ³Department of Hematology-Oncology, Ajou

University School of Medicine, Suwon 16499, Korea, Republic of, ⁴Department of Pathology, Ajou University School
of Medicine, Suwon 16499, Korea, Republic of, ⁵Institute on Aging, Ajou University Medical Center, Suwon 16499,
Korea, Republic of

Cellular senescence can either support or inhibit cancer progression. Here, we showed that intratumoral infiltration
of CD8+ T cells was negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC).

Gene expression analysis revealed increased expression of CXCL12 and CSF1 in senescent tumor cells. Senescent
tumor cells inhibited CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induced a loss of

CXCR4 in T cells, resulting in impaired directional migration. CSF1 from senescent tumor cells enhanced monocyte
differentiation into M2 macrophages, which are involved in T cell exhaustion. Neutralization of CXCL12/CSF1

increased the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent
tumor cells enhanced T cell infiltration and resulted in reducing the number and size of tumors in AOM/DSS-

induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting non-senescent
tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.