4.8 Article

Anti-CD40 predominates over anti-CTLA-4 to provide enhanced antitumor response of DC-CIK cells in renal cell carcinoma

Journal

FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.925633

Keywords

cytokine-induced killer cells; immunotherapy; renal cell carcinoma; CD40; CTLA-4

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The study found that anti-CD40 antibody can increase the number of CD3+CD56+ effector cells in CIK cells by promoting the maturation and activation of dendritic cells. In addition, anti-CD40 antibody can also increase the expression of CTLA-4 in CIK cells. For the antitumor response of DC-CIK cells against renal cell carcinoma cells, anti-CD40 antibody is superior to anti-CTLA-4 antibody. The CTLA-4 inhibitor ipilimumab can significantly increase the proportion of CD3+CD56+ cells in DC-CIK cells.
Cytokine-induced killer cells (CIK) in combination with dendritic cells (DCs) have shown favorable outcomes in renal cell carcinoma (RCC), yet some patients exhibit recurrence or no response to this therapy. In a broader perspective, enhancing the antitumor response of DC-CIK cells may help to address this issue. Considering this, herein, we investigated the effect of anti-CD40 and anti-CTLA-4 antibodies on the antitumor response of DC-CIK cells against RCC cell lines. Our analysis showed that, a) anti-CD40 antibody (G28.5) increased the CD3+CD56+ effector cells of CIK cells by promoting the maturation and activation of DCs, b) G28.5 also increased CTLA-4 expression in CIK cells via DCs, but the increase could be hindered by the CTLA-4 inhibitor (ipilimumab), c) adding ipilimumab was also able to significantly increase the proportion of CD3+CD56+ cells in DC-CIK cells, d) anti-CD40 antibodies predominated over anti-CTLA-4 antibodies for cytotoxicity, apoptotic effect and IFN-gamma secretion of DC-CIK cells against RCC cells, e) after ipilimumab treatment, the population of Tregs in CIK cells remained unaffected, but ipilimumab combined with G28.5 significantly reduced the expression of CD28 in CIK cells. Taken together, we suggest that the agonistic anti-CD40 antibody rather than CTLA-4 inhibitor may improve the antitumor response of DC-CIK cells, particularly in RCC. In addition, we pointed towards the yet to be known contribution of CD28 in the crosstalk between anti-CTLA-4 and CIK cells.

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