SIRPα and PD1 expression on tumor-associated macrophage predict prognosis of intrahepatic cholangiocarcinoma

Abstract

Background The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients. Methods We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para‐tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured. Results Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα+ or PD1+ TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non‐HBV‐infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis. Conclusion Hyperactivated CD47/SIRPα and PD1/PD‐L1 signals in CD68+ TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.

Identification of macrophage correlated biomarkers to predict the prognosis in patients with intrahepatic cholangiocarcinoma

“…The percentage of macrophages in the total number of immune cells increased significantly. The increased macrophage infiltration in ICCs was also confirmed by IHC, which is consistent with our previous study ( 25 ). Molecularly, macrophages can be divided into two types, namely M1- and M2-like macrophages and these cells are involved in anti-tumor activity and immunosuppressive tumor promotion ( 35 , 36 ).…”

“…If follow-up evaluations revealed metastatic disease and/or local recurrences, other therapies were applied, including conventional therapies (surgery, chemotherapy, and radiotherapy) as well as targeted and immunotherapy. Disease-free survival (DFS) was calculated from the date of surgery to the time of recurrence or metastasis, and patients who were alive and in a stable state were censored at the time of last contact ( 25 – 27 ). Overall survival (OS) was calculated from the date of surgery to the time of death, and patients who were alive at the time of last contact were censored ( 25 – 27 ).…”

“…Disease-free survival (DFS) was calculated from the date of surgery to the time of recurrence or metastasis, and patients who were alive and in a stable state were censored at the time of last contact ( 25 – 27 ). Overall survival (OS) was calculated from the date of surgery to the time of death, and patients who were alive at the time of last contact were censored ( 25 – 27 ). DFS and OS were calculated using the Kaplan–Meier analysis.…”

A New Serum Macrophage Checkpoint Biomarker for Innate Immunotherapy: Soluble Signal-Regulatory Protein Alpha (sSIRPα)

“…Firstly, high pre-treatment levels of sSIRPα could potentially signal a poor prognosis reflecting sSIRPα constitutively released by high numbers of TAMs. This is supported by SIRPα being constitutively released by MDMs and by recent evidence linking high SIRPα expression to poor survival in sev-eral tumors [11,[21][22][23][24]. Secondly, a rise in sSIRPα levels after initiation of immunotherapy may reflect the level of immune activation achieved, and thus predict the successfulness of the treatment.…”

Natural killer cells: a promising immunotherapy for cancer

“…In normal conditions, a “don’t eat me” signal is expressed by erythroblasts that avoid phagocytosis by macrophages, whereas senescent red blood cells cease to have the ability to express CD47 and are engulfed by macrophages [ 33 – 35 ]. Other cancers also express CD47 to avoid phagocytosis by macrophages in the tumor microenvironment (TME) [ 27 , 36 , 37 ]. Furthermore, malignant cells express minimal levels of tumor-associated antigens, dislodge NK cell-activating receptor ligands, or alter the expression of MHC-I as well as costimulatory biomolecules to escape immune reactions [ 13 , 38 ].…”