IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer

Abstract

Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.

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“…Only simultaneous blockade of PD-1 and neutralization of IL-10 leads to improved survival and slowed tumor growth in OC. Compensatory release of IL-10 reduces the effectiveness of anti-PD-1 (or anti-PD-L1) monotherapy [26] Более высокие уровни IL-6 и VEGF-A в асцитической жидкости связаны с меньшей выживаемостью без прогрессирования Higher levels of IL-6 and VEGF-A in ascitic fluid are associated with lower progression-free survival [27] IL-6, TNF-α, 8-IP Уровни IL-6, 8-IP в асците по сравнению с содержанием в плазме выше, а TNF-αниже. В случае платинорезистентного и платинорефрактерного течения РЯ наблюдается дисрегуляция между окислителями, антиоксидантами и провоспалительными цитокинами Levels of IL-6, 8-IP in ascites compared with plasma levels are higher, and TNF-α levels are lower.…”