Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor.

The macrophage-associated molecule CD163 has been reported as a prognostic biomarker in different cancer types, but its role in colorectal cancer (CRC) is unclear. We studied CD163 in the tumor microenvironment and circulation of patients with CRC in relation to clinicopathological parameters. An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum sCD163 levels and multiparameter flow cytometry was used to study the peripheral blood monocytes and their CD163 expression in CRC patients (N = 78) and healthy donors (N = 50). The distribution of tumor-associated macrophages (TAMs) was studied in primary colorectal tumors with multiplex immunofluorescence. We showed that CRC patients with above-median sCD163 level had a shorter overall survival (OS, p = 0.035) as well as disease-free survival (DFS, p = 0.005). The above-median sCD163 remained significantly associated with a shorter DFS in the multivariate analysis (p = 0.049). Moreover, a shorter OS was observed in CRC patients with an above-median total monocyte percentage (p = 0.007). The number and phenotype of the stromal and intraepithelial TAMs in colorectal tumors were not associated with clinical outcome. In conclusion, sCD163 and monocytes in the circulation may be potential prognostic biomarkers in CRC patients, whereas TAMs in the tumor showed no association with clinical outcome. Thus, our results emphasize the importance of the innate systemic immune response in CRC disease progression.

Natural Killer (NK) cells are essential in the biological fight against cancer and intracellular pathogens, and their level of activity has in many settings been used as a biomarker for a functional immune response. Currently, NK cell activity is measured using either ⁵¹Cr-release assays or flow cytometry based assays revealing the cells´ cytotoxic capacity or by stimulating them to produce cytokines. Although very effective, these are cumbersome techniques not suitable for high volume clinical laboratories. Recently, an assay has been introduced to measure NK cell activity in a simple and standardized manner. Following stimulation of NK cells in whole blood with a recombinant protein, it utilizes the concentration of IFNγ released to the plasma as a surrogate marker for NK cell activity. However, whole blood holds several sources of IFNγ which may blur the results and hamper the interpretation of the test. Therefore, the present study aimed at analyzing how specifically the test is measuring the activity of NK cells. Intracellular flow cytometry showed that NK cells, T cells, and Natural Killer T (NKT) cells were producing IFNγ in the assay, however when analyzing the distribution of lymphocytes in the IFNγ-expressing subset, the proportion of NK cells far exceeded the percentage of T-, and NKT cells (p < .0001). Hence, our data indicate that the readout of the test was indicative of the NK cells´ ability to mount a response and thus the results may pave the way for the assay to become applicable in the clinical setting as an estimate of NK cell activity for both diagnostic and prognostic purposes.