Immune-Related Gene Expression and Cytokine Secretion Is Reduced Among African American Colon Cancer Patients

Abstract

Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could be contributive to disparities observed between these populations. Methods: We examined gene expression of tumor and non-tumor adjacent tissues from AA and CA by whole transcriptome sequencing, and generated scores for immune cell populations by NanoString. In addition, we utilized “The Cancer Genome Atlas” (TCGA) database from AA and CA as a validation cohort. Finally, we measured the secretion of cytokines characteristic of effector T helper cell (T h ) subsets by ELISA using plasma from each AA and CA participant. Results: Colon tumors from AA patients showed significant fold-change increase in gene expression when compared to CA for FOXP3 (6.22 vs. 3.22), IL1B (103 vs. 11.4) and IL8 (220 vs. 28.9) ( p < 0.05). In contrast, among CA we observed statistically higher gene expression of markers associated with antitumor activity such as GZMB (Granzyme B), IFNG and the immunotherapy targets PDL1 ( CD274 ) and CTLA4 ( p < 0.05). TCGA data validated our observed higher gene expression of GZMB and PDL1 in CA patients when compared to AA. Notably, our observations on immune cell populations show that AA tumors have significantly higher number of exhausted CD8+ cells ( p < 0.01), mast cells ( p < 0.02) and increased T regulatory cells when compared to CA. AA colon cancer patients differed from CA in cytokine production patterns in plasma (i.e., reduced IL-12). Conclusions: Our study demonstrates significant differences of the immunological profiles of colon tumors from AA compared to CA that suggest a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such, these immune differences could be mitigated through population-specific therapeutic approaches.

Preinvasive Colorectal Lesions of African Americans Display an Immunosuppressive Signature Compared to Caucasian Americans

“…Lower cytotoxic or effector T cell responses in CRCs of AAs vs. CAs have been observed in a few previous studies in colorectal cancers (16)(17)(18)(19). Basa et al (18) identified lower protein expression of granzyme B in CRCs of AAs compared to CAs.…”

Cancer Omics in Africa: Present and Prospects

“…Moreover, the differences between the two groups studied were also evident in the patterns of cytokine production in plasma. This work indicated the dissimilarities in colon cancer immune characteristics between AA and CA that may be implicated in insufficiency of proper immune defense mechanisms (47).…”

Impact of preoperative antibiotics and other variables on integrated microbiome-host transcriptomic data generated from colorectal cancer resections

“…The characteristics of the patients for the subset of samples analyzed compared to that of the total collection of archived sporadic CRC samples (2010-2020) are shown in Table 2 . Since the samples in the subset were originally selected to provide Black/AA samples and “matched” White/EA samples for another transcriptomic profiling performed at a separate sequencing facility[ 25 ], there was significantly higher representation of Black/AA samples in this pilot study. Left-sided CRCs were also more highly represented in the subset compared to the overall collection.…”

“…Illumina paired-end sequencing was performed on the Miseq platform with versions v2.4 of the Miseq Control Software and of MiSeq Reporter, using a 600-cycle version 3 reagent kit. Illumina Miseq paired-end reads were aligned to human reference genome hg19 with bowtie2 and matching sequences were discarded as previously described[ 25 ]. All de-multiplexed, paired-end 16S rRNA gene sequence files along with associated metadata were deposited into the Gene Expression Omnibus under project accession number GSE165255.…”

“…CRC incidence and mortality has been persistently higher in Black/AA compared to all other races in the United States[ 23 , 24 ]. Paredes et al [ 25 ] recently reported that transcriptomic profiling of Black/AA compared to White/European Ancestry (EA) revealed reduced immune related gene expression in tumor samples and plasma cytokine levels collected from Black/AA CRC patients. We report here the results of this pilot study to investigate the effects of the tumor histology, preoperative antibiotics, laterality of CRC location, diabetes mellitus status and Black/AA race on microbiome and human transcriptomic data of CRC patients.…”