Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer

Abstract

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C‐X‐C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti‐PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)‐induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity

“…On the other hand, microsatellite stable (MSS) tumors have fewer neoantigens, lower immune checkpoints expression and immune infiltration, and acquire resistance to immune checkpoint inhibitors (Sahin et al, 2019). In contrast to the above studies suggesting a correlation between senescence and MSI tumors, a recent study has reported that MSS CRC tissues displaying senescent epithelial cell accumulation are associated with low immune cell infiltration (Choi et al, 2021). For instance, p16 positive tissues showed a low density of intratumoral CD8 T cells infiltration, whereas p16 negative tissues showed higher CD8 T cells infiltration.…”

“…For instance, p16 positive tissues showed a low density of intratumoral CD8 T cells infiltration, whereas p16 negative tissues showed higher CD8 T cells infiltration. Senescent cells secreted CXCL12 inhibiting CD8 T cell infiltration and CSF1 induced differentiation of monocytes into M2 macrophages ( Choi et al, 2021 ). In addition, inhibiting these two SASP molecules enhanced the effect of an immune checkpoint inhibitor (anti-PD-1) in allograft tumors ( Choi et al, 2021 ).…”

“…Senescent cells secreted CXCL12 inhibiting CD8 T cell infiltration and CSF1 induced differentiation of monocytes into M2 macrophages ( Choi et al, 2021 ). In addition, inhibiting these two SASP molecules enhanced the effect of an immune checkpoint inhibitor (anti-PD-1) in allograft tumors ( Choi et al, 2021 ). Therefore, it could be better for future studies to compare MSI with MSS in terms of their response to senescence inducers as well as immune scoring in tumor tissues from patients treated with a chemotherapy that is known to induce senescence.…”

CAR T Cell Therapy’s Potential for Pediatric Brain Tumors

“…However, tumors often express specific chemokines that deregulate the immune response. For instance, a high concentration of CXCL12 in the TME induces CXCR4 downregulation in T cells, which prevents CD8 + T cell tumor infiltration [77]. In adult GBM, CCR4 chemokine ligands are often upregulated, which supports CCR4 + regulatory T cell homing in the TME [78].…”

Cucurbitacin B Controls M2 Macrophage Polarization to Suppresses Metastasis via Targeting JAK-2/STAT3 Signalling Pathway

“…In respond to T helper type 2(Th2) cytokines such IL-4 and IL-13 results in alternative activation(M2), characterized by increase of mannose receptor (CD206), increased arginase-1 (Arg-1), found in in ammatory zone (Fizz-1), chitinase-like 3(Ym-1), Chemokine (CCL2) [9]. More importantly, increasing the number of M2 macrophages is a vital marker of CRC and is directly associated with poor clinical prognosis [10,11]. Thus, it is paramount to extensively and intensively understand the relationship between macrophage in ltration and colorectal patients' tumor progression, for the development of effective therapeutic strategies.…”