Predictive and prognostic effect of ABO blood group on immune checkpoint inhibitors

To the best of our knowledge, this is the first study to examine the presence of different blood group antigens and the response to immunotherapy. According to our findings, in patients with advanced malignant melanoma, patients with a blood group containing the B antigen respond better to ICIs and survival is significantly longer.

In previous studies examining the relationship between blood group and malignant melanoma, blood group A was found to be associated with the incidence of cutaneous malignant melanoma. Moreover, patients with blood group A were more likely to experience metastasis in cutaneous malignant melanoma, whereas this association was not detected in groups AB and B [5]. In another study, a positive correlation was found between O blood type and the incidence of malignant melanoma [6]. In contrast, two other studies show that blood group O prevents tumor spread [7, 8]. A study in patients with ovarian cancer showed that patients with blood group B had worse survival than those with non-B blood groups [9]. In addition, survival was worse in the B antigen group (B/AB) and the non-B antigen (A/O) group. A non-O blood group was shown to be associated with reduced OS in 900 patients undergoing resection for renal cell carcinoma [10]. No correlation was found between the blood group and prognosis of 404 patients who underwent resection for esophageal carcinoma [11].

The confusing relationship between immunotherapy and blood groups has been speculated about for a long time. In a short communication written in 1981, it was thought that levamisole, which was used as an antiparasitic agent and immunostimulant in the treatment of primary lung cancer at that time, achieved this effect by increasing the Th1 lymphocyte-related immune response and decreasing the Th2 lymphocyte-related response [12]. Lung cancer patients with O or Rh-negative blood groups treated with levamisole had significantly reduced overall survival. Furthermore, Rh-negative patients showed worse survival than Rh-positive patients. In our study, although survival was numerically worse in the Rh-negative patients in the B antigen group, the difference was not statistically significant. The reason it did not reach statistical significance may have been the small number of patients.

PROSTVAC-VF, a cancer vaccine, is an immunotherapy undergoing phase III clinical studies for the treatment of advanced prostate cancer [13]. It was found that patients with blood group B (median 38 months) and O (median 27.6 months) are associated with longer median survival than patients with group A (median 15.8 months) and AB (median 21.7 months) [14]. The low number of patients in that study, especially those with B and AB blood groups, may complicate the evaluation. Similar to that study, the presence of B antigen (B/AB) was associated with longer PFS and OS and objective response rate in our study. However, prospective studies with larger number of patients with different cancer types are needed to clearly explain this situation.

Blood group antigens are found on receptors such as integrins, cadherins, epidermal growth factor, and CD44 that control cell proliferation, resistance to apoptosis, and adhesion [15]. Inhibition of integrin in cancer cells results in local PD-L1 reduction and reduction in primary tumor growth [16]. Different blood group antigens, especially expressed on integrin, may decrease PDL-1 production differently by an unknown mechanism and may cause a different response to immunotherapy. Blood group antigens may also play a role in the effect of inflammation-soluble intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF- α ) in plasma [17, 18]. In a preclinical melanoma model, TNF- α facilitated tumor growth by acting through the TNFR1 pathway, disrupting the infiltration of CD8+T lymphocytes into the tumor microenvironment [19]. TNFR1 blockade enhances the efficacy of anti-PD-1 therapy. Preventing TNF- α upregulation of PDL-1 expression by CD8+ tumor infiltrating lymphocytes causes reappearance of anti-tumor immune response and prevents anti-PD-1 resistance [20]. Although the mechanism of action is unknown, the different effects of ABO blood group antigens on the TNF- α response may affect the relationship between TNF- α and PDL-1 at different rates, thereby changing the response to immunotherapy. However, these hypotheses need to be clarified by experimental studies.

Approximately one-half of cutaneous melanomas have a V600 mutation in the BRAF gene. In our study, the BRAF mutation rate was 24%. This difference may have been due to geographical and ethnic differences. In patients with BRAF V600 mutation-negative, stage IV melanoma, PD-1 inhibitor monotherapy or a combination of nivolumab and ipilimumab are the preferred options for immunotherapy. Clinical studies are needed to determine which disease subgroups benefit more from the combination versus monotherapies and what the optimal dose and schedule for the combination is. Immunotherapy is used in the BRAF V600 mutation-positive patient group because of its ability to provide long-term treatment-free survival. However, studies are needed to determine the optimal treatment sequence in this patient group. Although the efficacy of immunotherapy appears to be less after progression with a BRAF inhibitor, prospective data are needed for combination therapy or monotherapy in this situation. In the present study, all BRAF mutant patients had received a BRAF/MEK inhibitor combination and BRAF wild patients used temozolomide in the first line treatment. There was no difference in OS or PFS for immunotherapy between the BRAF mutant and non-mutant group.

Although our study was the first to examine the immunotherapy response with ABO blood groups, it had some limitations. The most important limitation of the study was that it was retrospective. The number of patients was relatively small. Especially the presence of two patients with the AB blood group made the evaluation difficult. In addition, due to the health policies in this country, nivolumab treatment was used in the second line at the earliest. Patients who received nivolumab treatment in the third and fourth lines were also included in the study. However, due to the small number of patients in the subgroups, a comparison between the different treatment lines was not possible.

5. Conclusion

In the present study, we aimed to draw attention to the relationship between blood groups and immunotherapy responses in advanced melanoma patients treated with nivolumab. Presence of the B antigen in advanced stage melanoma patients was an important advantage in terms of survival. Certain estimates have been made for the underlying mechanism. However, prospective studies are needed to reveal the clear mechanism and to determine the ABO blood group-immunotherapy response in different cancer types. Our study will guide other studies in this respect.