Abstract
Immune checkpoint blockers (ICB) have emerged as a promising new class of antitumor agents which significantly change the treatment landscape in a range of tumors; however, cancer patients benefited from ICB-based immunotherapy remains limited, scoring the need to explore the combination treatments with synergistic mechanisms of action. Axl receptor tyrosine kinase critically involves in the carcinogenesis of multiple cancers due to its dual roles in both promoting cancer invasion and metastasis and suppressing myeloid cell activation and function. Here, we found that Axl inhibition by tyrosine kinase inhibitors induces antitumor efficacy critically depending on immune effector mechanisms in two highly clinical relevant murine tumor models. Mechanistic investigation defined that Axl inhibition reprograms the immunological microenvironment leading to the increased proliferation, activation and effector function of tumor-infiltrating CD4+ and CD8+ T cells possibly through preferential accumulation and activation of CD103+ cross-presenting dendritic cells. More importantly, we show that Axl inhibition induces an adaptive immune resistance evidenced by unregulated PD-L1 expression on tumor cells and combined Axl inhibition with PD-1 blockade mounts a potent synergistic antitumor efficacy leading to tumor eradication. Thus, Axl-directed therapy in Axl expressing tumors could hold a great potential to subvert the innate and/or adaptive resistance to and broaden the coverage of population benefited from ICB-based immunotherapy.
Highlights
IntroductionCancer immunotherapy is becoming reinvigorated [1]. In this regard, Immune checkpoint blockers (ICB) targeting programmed death-1 (PD-1) and its ligand PD-L1 have produced an unprecedented clinical benefit in cancer patients and been approved by Food and Drug Administration for treating melanoma, Hodgkin lymphoma, Merkel cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma and urothelial carcinoma with a rapidly growing list of indication [2]
In recent years, cancer immunotherapy is becoming reinvigorated [1]
Further mechanistic investigation defined that Axl inhibition reprograms the immunological microenvironment leading to the increased proliferation, activation and effector function of tumor-infiltrating CD4+ and CD8+T cells possibly through preferential accumulation and activation of CD103+ CD11c+MHC-II+ DCs (cDCs), which is in favor of antitumor immune response
Summary
Cancer immunotherapy is becoming reinvigorated [1]. In this regard, ICB targeting programmed death-1 (PD-1) and its ligand PD-L1 have produced an unprecedented clinical benefit in cancer patients and been approved by Food and Drug Administration for treating melanoma, Hodgkin lymphoma, Merkel cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma and urothelial carcinoma with a rapidly growing list of indication [2]. Aguilera et al recently demonstrated that Axl is an essential gene expressed in mouse tumors refractory to combinatorial irradiation and immunotherapy (anti-PD-1 and/or anti-CTLA4) and its knockdown reprograms the immunological microenvironment leading to tumor sensitization [19]; Hugo et al reported that Axl is a key gene expressed in tumors from patients innately resistant to anti-PD-1 immunotherapy through analysis of the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies [20], indicating that Axl may modulate innate immune cells to dampen the adaptive antitumor immune responses reinvigorated by anti-PD-1 immunotherapy other than its intrinsic protumor roles in tumor cells. Disabling Axl signaling may promote engagement of adaptive immunity and complement ICB-based immunotherapy
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