Investigating patient and tumor features that underlie well-established CRC racial disparities holds promise to uncover potential deficiencies in the tumor immune response of AA versus EA patients. Defining underlying cellular and molecular racial factors that promote poorer outcomes in AA patients may enable the design of therapeutic interventions to overcome disparities. Emerging studies suggest alterations in T cell presence and function in AAs may contribute to CRC disparities.(4, 26) Our group previously reported that low immune infiltrate in tumors from AA patients was more predictive of poor outcome.(4) To extend this line of investigation, we applied an immunogenomic analysis strategy to investigate CRC racial differences in gene expression data from TCGA.
Our evaluation of the tumor immune microenvironment revealed striking differences between AA and EA CRCs. AA CRC tumors displayed a decreased fraction of macrophages and CD8 T cells and an increased fraction of B cells compared with EA tumors in the tumor microenvironment, possibly suggesting a more favorable immune environment for anti-tumor immunity in EA cancers. The cellular outcomes persisted when controlling for sex, age and disease stage. Further differences were identified with respect to the expression of immunostimulatory and immunoinhibitory genes as well as MHC class I and class II molecules. Gene expression analysis demonstrated increased expression of immune regulatory molecules in EA patients including genes encoding for PD-L1 and PD-1. While expression of these molecules could reflect a more suppressive environment, these changes may independently reflect a general enhanced immune infiltration present in these tumors. Interestingly, a prior report found that African ancestry has also been associated with decreased PDL-1 expression across cancer types including colorectal adenocarcinoma, breast cancer, head and neck squamous cell cancer and papillary thyroid cancer.(21) In addition, the elevated macrophages, particularly M1 macrophages, is suggestive of a more favorable immune environment in EA CRCs.
The reduced expression of MHC class I and II in AA patient tumors was striking. While loss of MHC class I and II expression may reflect alterations in antigen processing in tumor or professional antigen presenting cells, it could also simply reflect a general reduced immune infiltration into the tumor, especially in the possible reduction of IFNγ. Imaging studies defining MHC class I and II expression on different immune cells in the tumor will be necessary to address these possibilities. Given the critical role of tumoral antigen presentation in sustaining immune-based therapies (27–29), this finding is likely to be a key area of investigation for CRC racial disparities.
Seminal studies have established a strong relationship between increased peritumoral lymphocyte density and survival in CRC that exceeded the prognostic ability of TNM stage.11 Wallace and colleagues from our institution supported the association between lymphocyte density and survival yet also identified a subset of young AA patients who fared poorly despite a high lymphocyte density suggesting that lymphocyte function and/or gene expression rather than density of cells may play a role in survival.6 In addition, previous work by Basa and colleagues demonstrated a significant decrease in granzyme B + infiltration for AA CRCs suggesting a decreased cytotoxic effect.17 Our current analysis builds on these observations suggesting that the antigen presentation process and T cell activity are globally reduced in AA patients resulting in less active cytotoxic T cells. The decreased expression of checkpoint mediators in AA tumors suggests that AA tumors compared with EA tumors have not activated specific T cell inhibitory pathways.
The results of this study must be evaluated in the context of its data source and study design. While TCGA is among the largest repositories of molecular cancer data available, the sample size specific to colorectal adenocarcinoma is small with the majority of tumor samples collected from EA patients. Though a wealth of molecular information is available through TCGA, certain information such as microsatellite stability are not readily available. Additionally, granular, patient-level socioeconomic and clinical data regarding patient treatment is unavailable in TCGA which allows for the possibility that differences in survival could be attributable to differences in access to care and treatment received. With respect to racial differences in progression free survival and tumor immune response, the mechanism by which racial differences in tumor immune response may underlie disparate clinical outcomes remains to be elucidated.