In the present study, our analysis identified three distinct cell clusters in CRC sample, namely T cells, myeloid cells and B cells. Notably, we observed that MIF signaling to CD74 + CD44 and CXCR4 displayed the highest probability of interaction in the B cell communication. Furthermore, we identified a set of six genes (GPR88, PTH1R, SFRP2, GPX3, ELFN1, and MS4A2) that exhibited prognostic significance in CRC. The prognostic differences between the two groups were found to be statistically significant in both the internal and external sets, indicating the potential utility of this gene set as a prognostic biomarker in CRC. We observed higher infiltration of the activated B cells, CD4 + T cells, and CD8 + T cells in the LR group, which was characterized with an inferior prognosis. The abundance of CD8 + T cells were highly correlated with plasmacytoid and activated dendritic cells and follicular T helper cells.
In addition to active contribution in aging15, senescent cells are found to be widely present in neoplastic tissues16. Senescence can be driven by excessive oncogenic signaling or loss of certain tumor suppressor genes17. Excessive Ras activity can promote oncogene-induced senescence (OIS) in both murine and human fibroblasts, primarily through Rb and p53 dependent pathways. OIS results in a durable cell cycle arrest that can function as a tumor preventive mechanism, while activating tumor suppressor pathways and DNA damage response. OIS has been observed in several human pathologies, including early-stage prostate tumors, colon adenomas, astrocytoma, neurofibromas, and benign neoplasms of melanocytes. However, the interplay between tumor cells, senescent cells, and the immune system is still being explored. In vivo models of hepatocellular carcinoma have shown that senescence induction of liver tumor cells through the restoration of p53 promotes clearance of these cells by triggering the innate immune system18. The absence of p53, on the other hand, bypasses senescence, allowing hepatocytes to transform into cancer cells. These findings indicate that both pre- and post-tumor establishment senescence arrest can be beneficial in protecting against malignancies18. Accordingly, several drugs have been developed to promote senescence in neoplastic cells. For instance, CDK4/6 inhibitors are currently undergoing preclinical and clinical trials19. While cellular senescence can intrinsically suppress tumorigenesis in preneoplastic cells, the senescence-associated secretory phenotype factors produced by senescent cells can extrinsically promote tumor growth and metastasis20, 21. Studies have shown that the senescence-associated secretory phenotype factors can be temporally regulative, with early secrestion, such as TGF-β1 and TGF-β3, being immunosuppressive, and subsequent secretion consisting of pro-inflammatory cytokines, including IL-6, IL-1β, and IL-822, 23. Senescent stromal cells may influence tumorigenesis by secreting IL-6, which recruits myeloid suppressive cells to inhibit T-cell response against malignant cells. These findings suggest that the regulation of senescence-associated secretory phenotype factors potentially providing a therapeutic window for targeting senescent cells in cancer.
In models of breast carcinoma, a novel approach has been demonstrated whereby CDK4/6 inhibition not only induces tumor cell cycle arrest but also stimulates cytotoxic T cell-mediated clearance of tumor cells by activating endogenous retroviral elements24. CDK4/6 inhibition failed to curb the expansion of T cells. Moreover, it was observed that the effect of PD-1 inhibition is augmented by CDK4/6 inhibition, thereby suggesting a potential synergy between these two pathways25. The stability of PD-L1 is regulated by the cullin 3-SPOP E3 ligase, which is responsible for proteasome-mediated degradation of cyclin D-CDK4. T regulatory cells are more sensitive to CDK4/6 inhibition because of their elevated expression of CDK6 in comparison to other T cell subtypes. This results in upregulation of cytotoxic CD8 + T cells to respond to cancer cells26. These findings collectively suggest that a combined approach of CDK4/6 inhibitors and PD-L1 immune blockade may enhance the effectiveness of immunotherapies in cancer patients.
The induction of cellular senescence is gradually recognized as a potent strategy to suppress the progression of CRC. In CRC cells, it has been observed that Cucurbitacin E (CE) exerts pro-senescent effects by attenuating the expression of TFAP4. On the level of mechanism, CE triggered the elevation in miR-371b-5p levels, which results in a marked repression of TFAP427. Baicalin, a natural flavonoid glycoside, activates DEPP-mediated downstream Ras/ERK pathway, leading to senescence of CRC cells. A variety of cellular senescence regulating substance was found to effective in CRC treatment in vitro28, 29. Molecular researches are warranted to determine the exact mechanism underpinning the tumor suppressive phenotype of cellular senescence in CRC, which may coordinate with surgical approaches to facilitate the CRC recovery.